Is COMP p.Val697Ala (c.2090T>C) pathogenic?

COMP p.Val697Ala (c.2090T>C) is classified Uncertain significance in COMP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-04). AlphaMissense: likely benign (0.3208); Very rare (popmax 0.00203%, nfe); Associated with Inborn genetic diseases.

What condition is associated with COMP p.Val697Ala (c.2090T>C)?

COMP p.Val697Ala (c.2090T>C) is associated with Inborn genetic diseases (ClinVar).

How common is COMP p.Val697Ala (c.2090T>C) in the general population?

COMP p.Val697Ala (c.2090T>C) is very rare (popmax 0.00203%, nfe) (gnomAD).

What do computational predictors say about COMP p.Val697Ala (c.2090T>C)?

AlphaMissense predicts likely benign (score 0.3208) — an in-silico prediction, not a clinical call.

COMP p.Val697Ala

c.2090T>C · rs764317174 · VCV1895964

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3208 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00203%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3208	likely benign
REVEL	0.571	indeterminate
SaProt	LLR -7.55	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	23.4	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

Grpmax group 0.00203% European (non-Finnish) · 24/1,179,942 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00162% 26/1,607,276 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00203%	49,164
Remaining individualsnot grpmax-eligible	0.0016%	62,440
African / African-American	0.00134%	74,906

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: COMP
Protein: p.Val697Ala
Coding: c.2090T>C
MANE Select: NM_000095
dbSNP: rs764317174
Type: single nucleotide variant
Location: chr19:18783191 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 697: the tsp c-terminal domain; the 'mediates cell survival and induction of the iap family of survival proteins' region; a β-strand; a disulfide bond

Full COMP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COMP p.Val697Met Uncertain significance ★ ⚠ same residue
COMP p.Arg247Ser Uncertain significance ★★ ⚠ same condition
COMP p.Arg352Trp Uncertain significance ★★ ⚠ same condition
COMP p.Arg379Gln Uncertain significance ★★ ⚠ same condition
COMP p.Arg381Leu Uncertain significance ★★ ⚠ same condition
COMP p.Arg665Trp Uncertain significance ★★ ⚠ same condition
COMP p.Arg689Trp Uncertain significance ★★ ⚠ same condition
COMP p.Arg721His 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/comp-p-val697ala (accessed [today's date]).

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