Is SHOC2 p.Pro565= (c.1695T>A) pathogenic?

SHOC2 p.Pro565= (c.1695T>A) is classified Likely benign in SHOC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-29). Very rare (popmax 0.00314%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with SHOC2 p.Pro565= (c.1695T>A)?

SHOC2 p.Pro565= (c.1695T>A) is associated with Cardiovascular phenotype, RASopathy (ClinVar).

How common is SHOC2 p.Pro565= (c.1695T>A) in the general population?

SHOC2 p.Pro565= (c.1695T>A) is very rare (popmax 0.00314%, nfe) (gnomAD).

SHOC2 p.Pro565=

c.1695T>A · rs770183343 · VCV1778224

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00314%, 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 2	GERP -1.1, phastCons 1
Overall
CADD	8.798	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00314% European (non-Finnish) · 37/1,179,958 alleles

Filtering AF 0.00231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00242% 39/1,613,932 alleles · very rare exomes 38/1,461,808 · genomes 1/152,124 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00314%	31,891
Remaining individualsnot grpmax-eligible	0.0016%	62,482
African / African-American	0.00134%	74,900

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.Pro565=
Coding: c.1695T>A
MANE Select: NM_007373
dbSNP: rs770183343
Type: single nucleotide variant
Location: chr10:111011764 (GRCh38)
Gene constraint: LOEUF 0.201 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.00 · 13 PDB
Residue 565: 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

Also linked: RASopathy

Similar variants

SHOC2 p.Pro565Thr Uncertain significance ★ ⚠ same residue
SHOC2 p.Pro565fs 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-pro565 (accessed [today's date]).

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