Is SHOC2 p.Ser57Phe (c.170C>T) pathogenic?

SHOC2 p.Ser57Phe (c.170C>T) is classified Conflicting classifications of pathogenicity in SHOC2 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.1276); Ultra-rare (popmax 0.0165%, mid); Associated with Cardiovascular phenotype.

What condition is associated with SHOC2 p.Ser57Phe (c.170C>T)?

SHOC2 p.Ser57Phe (c.170C>T) is associated with Cardiovascular phenotype, RASopathy, Noonan syndrome-like disorder with loose anagen hair 1 (ClinVar).

How common is SHOC2 p.Ser57Phe (c.170C>T) in the general population?

SHOC2 p.Ser57Phe (c.170C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about SHOC2 p.Ser57Phe (c.170C>T)?

AlphaMissense predicts likely benign (score 0.1276) — an in-silico prediction, not a clinical call.

SHOC2 p.Ser57Phe

c.170C>T · rs536611911 · VCV179760

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1276 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

ClinGen expert panel — RASopathy VCEP

Uncertain Significance for RASopathy. Applied ACMG criteria (verbatim):

PP2

Curation rationale (ClinGen, verbatim)

The c.170C>T (p.Ser57Phe) variant in SHOC2 was present in 0.0055% (5/35376 CI 95%) of Latino alleles in gnomAD v2.1.1 (BS1 not met; PMID: 29493581). It has been identified in healthy individuals without clinical features of a RASopathy, but this information does not meet the current criteria to apply BS2 (Ambry Genetics internal data, Baylor Genetics internal data). The variant is located in SHOC2, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, the clinical significance of the p.Ser57Phe variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.1276	likely benign
REVEL	0.427	indeterminate
SaProt	LLR -9.30	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 376 bp · p 0.042 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00539% 87/1,614,030 alleles · ultra-rare exomes 82/1,461,796 · genomes 5/152,234 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Admixed American	0.015%	6,665
South Asian	0.00659%	15,181
Remaining individualsnot grpmax-eligible	0.0064%	15,627
European (non-Finnish)	0.00568%	17,612

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SHOC2
Protein: p.Ser57Phe
Coding: c.170C>T
MANE Select: NM_007373
dbSNP: rs536611911
Type: single nucleotide variant
Location: chr10:110964528 (GRCh38)
Gene constraint: LOEUF 0.201 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.00 · 13 PDB
Residue 57: the 'disordered' region

Full SHOC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: RASopathy Noonan syndrome-like disorder with loose anagen hair 1

Similar variants

SHOC2 p.Ser57Pro Uncertain significance ★★ ⚠ same residue
SHOC2 p.Ser57Thr Uncertain significance ★★ ⚠ same residue
SHOC2 p.Ser57= Likely benign ★★ same residue
SHOC2 p.Met173Ile Pathogenic ★★★ ⚠ same condition
SHOC2 p.Ser2Gly Pathogenic ★★★ ⚠ same condition
SHOC2 c.-1C>T Uncertain significance ★★★ same condition
SHOC2 p.Tyr189Phe Uncertain significance ★★★ ⚠ same condition
SHOC2 c.1423-7C>T Benign ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/shoc2-p-ser57phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown