Is SHOC2 p.Ser57= (c.171C>T) pathogenic?

SHOC2 p.Ser57= (c.171C>T) is classified Likely benign in SHOC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-02). Ultra-rare (popmax 0.0329%, mid); Associated with RASopathy.

What condition is associated with SHOC2 p.Ser57= (c.171C>T)?

SHOC2 p.Ser57= (c.171C>T) is associated with RASopathy (ClinVar).

How common is SHOC2 p.Ser57= (c.171C>T) in the general population?

SHOC2 p.Ser57= (c.171C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

SHOC2 p.Ser57=

c.171C>T · rs1554857645 · VCV505339

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Conditions

RASopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.023	GERP -1.1, phastCons 0.8
Overall
CADD	8.724	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,082 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.000867% 14/1,613,928 alleles · ultra-rare exomes 12/1,461,798 · genomes 2/152,130 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,041
European (non-Finnish)	0.00102%	98,334

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.Ser57=
Coding: c.171C>T
MANE Select: NM_007373
dbSNP: rs1554857645
Type: single nucleotide variant
Location: chr10:110964529 (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

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

Similar variants

SHOC2 p.Ser57Pro Uncertain significance ★★ ⚠ same residue
SHOC2 p.Ser57Thr Uncertain significance ★★ ⚠ same residue
SHOC2 p.Ser57Phe Conflicting classifications of pathogenicity ★ ⚠ 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-ser57 (accessed [today's date]).

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