Is SHOC2 p.Ser352Phe (c.1055C>T) pathogenic?

SHOC2 p.Ser352Phe (c.1055C>T) is classified Uncertain significance in SHOC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-30). AlphaMissense: ambiguous (0.4592); Very rare (popmax 6.2e-05%); Associated with RASopathy.

What condition is associated with SHOC2 p.Ser352Phe (c.1055C>T)?

SHOC2 p.Ser352Phe (c.1055C>T) is associated with RASopathy (ClinVar).

How common is SHOC2 p.Ser352Phe (c.1055C>T) in the general population?

SHOC2 p.Ser352Phe (c.1055C>T) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about SHOC2 p.Ser352Phe (c.1055C>T)?

AlphaMissense predicts ambiguous (score 0.4592) — an in-silico prediction, not a clinical call.

SHOC2 p.Ser352Phe

c.1055C>T · rs1848437546 · VCV1309428

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4592 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.4592	ambiguous
REVEL	0.306	indeterminate
SaProt	LLR -8.95	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.32	constrained · MANE · 22 kb · p 3.9e-17 · regional, not allelic
Overall
CADD	26.2	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 6.2e-05%

Overall 6.2e-05% 1/1,612,972 alleles · very rare exomes 1/1,460,692 · genomes 0/152,280 · joint denominator

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.Ser352Phe
Coding: c.1055C>T
MANE Select: NM_007373
dbSNP: rs1848437546
Type: single nucleotide variant
Location: chr10:111004688 (GRCh38)
Gene constraint: LOEUF 0.201 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.00 · 13 PDB
Residue 352: a turn

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.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
SHOC2 c.1540+8C>T Likely benign ★★★ same condition
SHOC2 p.Ala298= 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-ser352phe (accessed [today's date]).

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