Is SHOC2 p.Val405= (c.1215A>G) pathogenic?

SHOC2 p.Val405= (c.1215A>G) is classified Likely benign in SHOC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-02-06). Very rare (popmax 0.00136%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with SHOC2 p.Val405= (c.1215A>G)?

SHOC2 p.Val405= (c.1215A>G) is associated with Cardiovascular phenotype, RASopathy, Noonan syndrome-like disorder with loose anagen hair 1 (ClinVar).

How common is SHOC2 p.Val405= (c.1215A>G) in the general population?

SHOC2 p.Val405= (c.1215A>G) is very rare (popmax 0.00136%, nfe) (gnomAD).

SHOC2 p.Val405=

c.1215A>G · rs749123957 · VCV878756

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 0.6, phastCons 1
Overall
CADD	9.137	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00136% European (non-Finnish) · 16/1,179,728 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.000991% 16/1,613,756 alleles · very rare exomes 16/1,461,410 · genomes 0/152,346 · 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.Val405=
Coding: c.1215A>G
MANE Select: NM_007373
dbSNP: rs749123957
Type: single nucleotide variant
Location: chr10:111007584 (GRCh38)
Gene constraint: LOEUF 0.201 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.00 · 13 PDB

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 Noonan syndrome-like disorder with loose anagen hair 1

Similar variants

SHOC2 p.Val405Ile Uncertain significance ★ ⚠ same residue
SHOC2 p.Val405Leu 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-val405 (accessed [today's date]).

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