Is SHOC2 p.Ser57Pro (c.169T>C) pathogenic?

SHOC2 p.Ser57Pro (c.169T>C) is classified Uncertain significance in SHOC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-08). AlphaMissense: likely benign (0.0848); Ultra-rare (popmax 0.01%, amr); Associated with Cardiovascular phenotype.

What condition is associated with SHOC2 p.Ser57Pro (c.169T>C)?

SHOC2 p.Ser57Pro (c.169T>C) is associated with Cardiovascular phenotype, RASopathy (ClinVar).

How common is SHOC2 p.Ser57Pro (c.169T>C) in the general population?

SHOC2 p.Ser57Pro (c.169T>C) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about SHOC2 p.Ser57Pro (c.169T>C)?

AlphaMissense predicts likely benign (score 0.0848) — an in-silico prediction, not a clinical call.

SHOC2 p.Ser57Pro

c.169T>C · rs754709778 · VCV1508675

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0848 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0848	likely benign
REVEL	0.268	benign-leaning
SaProt	LLR -6.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 376 bp · p 0.042 · regional, not allelic
Overall
CADD	19.12	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/59,976 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000558% 9/1,613,814 alleles · ultra-rare exomes 8/1,461,802 · genomes 1/152,012 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,996
Remaining individualsnot grpmax-eligible	0.0032%	31,240
South Asian	0.0011%	91,084

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.Ser57Pro
Coding: c.169T>C
MANE Select: NM_007373
dbSNP: rs754709778
Type: single nucleotide variant
Location: chr10:110964527 (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

Similar variants

SHOC2 p.Ser57Thr Uncertain significance ★★ ⚠ same residue
SHOC2 p.Ser57= Likely benign ★★ 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-ser57pro (accessed [today's date]).

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