Is SHOC2 p.Ser4Arg (c.10A>C) pathogenic?

SHOC2 p.Ser4Arg (c.10A>C) is classified Benign in SHOC2 (ClinVar, Expert panel, 9 submitters; last evaluated 2024-09-17). AlphaMissense: likely benign (0.3345); Rare (popmax 0.208%, amr); Associated with RASopathy.

What condition is associated with SHOC2 p.Ser4Arg (c.10A>C)?

SHOC2 p.Ser4Arg (c.10A>C) is associated with RASopathy, Noonan syndrome-like disorder with loose anagen hair 1 (ClinVar).

How common is SHOC2 p.Ser4Arg (c.10A>C) in the general population?

SHOC2 p.Ser4Arg (c.10A>C) is rare (popmax 0.208%, amr) (gnomAD).

What do computational predictors say about SHOC2 p.Ser4Arg (c.10A>C)?

AlphaMissense predicts likely benign (score 0.3345) — an in-silico prediction, not a clinical call.

SHOC2 p.Ser4Arg

c.10A>C · rs397517231 · VCV40635

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.3345 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.208%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Benign for RASopathy. Applied ACMG criteria (verbatim):

BP5 BP4 BA1

Curation rationale (ClinGen, verbatim)

The c.10A>C variant in the SHOC2 gene is a missense variant predicted to cause substitution of serine by arginine at amino acid 4 (p.Ser4Arg). The highest filtering allele frequency in gnomAD v4.1.0 is 0.2286% (124/59742 alleles) in the Admixed American population and therefore meets this criterion (BA1). The computational predictor tool REVEL gives a score of 0.113 and does not predict a damaging effect on SHOC2 function (BP4). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM GTR Lab ID: 26957, 21766 internal data; ClinVar SCV000209046.7, SCV000062455.5). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP4, BP5 (Specification Version 2.1, 09/17/2024)

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

Computational evidence

Protein change
AlphaMissense	0.3345	likely benign
REVEL	0.113	moderately benign-leaning
SaProt	LLR -5.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.3	GERP 1.3, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 376 bp · p 0.042 · regional, not allelic
Overall
CADD	23.3	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 0.208% Admixed American · 124/59,742 alleles

Filtering AF 0.178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.167%

Overall 0.00775% 125/1,613,066 alleles · rare exomes 120/1,460,864 · genomes 5/152,202 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.208%	482
Remaining individualsnot grpmax-eligible	0.0016%	62,442

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.Ser4Arg
Coding: c.10A>C
MANE Select: NM_007373
dbSNP: rs397517231
Type: single nucleotide variant
Location: chr10:110964368 (GRCh38)
Gene constraint: LOEUF 0.201 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.00 · 13 PDB
Residue 4: 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

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

Similar variants

SHOC2 p.Ser4Gly Uncertain significance ★ ⚠ same residue
SHOC2 p.Ser4Asn Uncertain significance ★ ⚠ 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
SHOC2 c.1540+8C>A Likely 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-ser4arg (accessed [today's date]).

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