Is SHOC2 p.Val64= (c.192G>A) pathogenic?

SHOC2 p.Val64= (c.192G>A) is classified Likely benign in SHOC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-03-20). Very rare (popmax 0.00133%, afr); Associated with RASopathy.

What condition is associated with SHOC2 p.Val64= (c.192G>A)?

SHOC2 p.Val64= (c.192G>A) is associated with RASopathy (ClinVar).

How common is SHOC2 p.Val64= (c.192G>A) in the general population?

SHOC2 p.Val64= (c.192G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

SHOC2 p.Val64=

c.192G>A · rs1185076769 · VCV1658428

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

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 1.5	GERP -2.3, phastCons 1
Overall
CADD	7.683	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,022 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,614,078 alleles · very rare exomes 6/1,461,822 · genomes 0/152,256 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,022
European (non-Finnish)	0.000424%	236,001

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.Val64=
Coding: c.192G>A
MANE Select: NM_007373
dbSNP: rs1185076769
Type: single nucleotide variant
Location: chr10:110964550 (GRCh38)
Gene constraint: LOEUF 0.201 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.00 · 13 PDB
Residue 64: 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.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-val64 (accessed [today's date]).

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