Is SHOC2 p.Leu165= (c.495T>C) pathogenic?

SHOC2 p.Leu165= (c.495T>C) is classified Likely benign in SHOC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-22). Very rare (popmax 0.000678%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with SHOC2 p.Leu165= (c.495T>C)?

SHOC2 p.Leu165= (c.495T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is SHOC2 p.Leu165= (c.495T>C) in the general population?

SHOC2 p.Leu165= (c.495T>C) is very rare (popmax 0.000678%, nfe) (gnomAD).

SHOC2 p.Leu165=

c.495T>C · VCV3441504

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000678%, 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 -0.029	GERP 0.3, phastCons 0.92
Overall
CADD	7.219	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000678% European (non-Finnish) · 8/1,179,958 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,613,926 alleles · very rare exomes 7/1,461,790 · genomes 1/152,136 · 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.Leu165=
Coding: c.495T>C
MANE Select: NM_007373
Type: single nucleotide variant
Location: chr10:110964853 (GRCh38)
Gene constraint: LOEUF 0.201 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.00 · 13 PDB
Residue 165: an α-helix

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

Similar variants

SHOC2 p.Ala298Thr Uncertain significance ★★ ⚠ same condition
SHOC2 p.Ala304Thr Uncertain significance ★★ ⚠ same condition
SHOC2 p.Ala580Thr Uncertain significance ★★ ⚠ same condition
SHOC2 p.Arg366Gln Uncertain significance ★★ ⚠ same condition
SHOC2 p.Asn248Thr Uncertain significance ★★ ⚠ same condition
SHOC2 p.Asp210Asn Uncertain significance ★★ ⚠ same condition
SHOC2 p.Asp49Asn Uncertain significance ★★ ⚠ same condition
SHOC2 p.Gln229Lys Uncertain significance ★★ ⚠ 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-leu165 (accessed [today's date]).

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