Is SHOC2 p.Ser85Phe (c.254C>T) pathogenic?

SHOC2 p.Ser85Phe (c.254C>T) is classified Uncertain significance in SHOC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-23). AlphaMissense: likely benign (0.3158); Absent from gnomAD v4.1; Associated with RASopathy.

What condition is associated with SHOC2 p.Ser85Phe (c.254C>T)?

SHOC2 p.Ser85Phe (c.254C>T) is associated with RASopathy (ClinVar).

How common is SHOC2 p.Ser85Phe (c.254C>T) in the general population?

SHOC2 p.Ser85Phe (c.254C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SHOC2 p.Ser85Phe (c.254C>T)?

AlphaMissense predicts likely benign (score 0.3158) — an in-silico prediction, not a clinical call.

SHOC2 p.Ser85Phe

c.254C>T · rs1847637817 · VCV1025311

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.3158 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.3158	likely benign
REVEL	0.453	indeterminate
SaProt	LLR -6.68	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4	GERP 0.93, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 376 bp · p 0.042 · regional, not allelic
Overall
CADD	22.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SHOC2
Protein: p.Ser85Phe
Coding: c.254C>T
MANE Select: NM_007373
dbSNP: rs1847637817
Type: single nucleotide variant
Location: chr10:110964612 (GRCh38)
Gene constraint: LOEUF 0.201 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.00 · 13 PDB
Residue 85: 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.Ser85= 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
SHOC2 c.1540+8C>A Likely benign ★★★ same condition
SHOC2 c.1540+8C>T 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-ser85phe (accessed [today's date]).

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