Is COMP p.Val591Ile (c.1771G>A) pathogenic?

COMP p.Val591Ile (c.1771G>A) is classified Uncertain significance in COMP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-13). AlphaMissense: likely benign (0.0781); Ultra-rare (popmax 0.022%, sas); Associated with Inborn genetic diseases.

What condition is associated with COMP p.Val591Ile (c.1771G>A)?

COMP p.Val591Ile (c.1771G>A) is associated with Inborn genetic diseases (ClinVar).

How common is COMP p.Val591Ile (c.1771G>A) in the general population?

COMP p.Val591Ile (c.1771G>A) is ultra-rare (popmax 0.022%, sas) (gnomAD).

What do computational predictors say about COMP p.Val591Ile (c.1771G>A)?

AlphaMissense predicts likely benign (score 0.0781) — an in-silico prediction, not a clinical call.

COMP p.Val591Ile

c.1771G>A · rs781599665 · VCV3147935

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0781 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0781	likely benign
REVEL	0.273	benign-leaning
SaProt	LLR -9.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP -1.9, phastCons 0.3
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	21.0	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 0.022% South Asian · 20/91,082 alleles

Filtering AF 0.0145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00157% 23/1,461,864 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.022%	4,554
Remaining individualsnot grpmax-eligible	0.0048%	20,829

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.Val591Ile
Coding: c.1771G>A
MANE Select: NM_000095
dbSNP: rs781599665
Type: single nucleotide variant
Location: chr19:18785039 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 591: the tsp c-terminal domain; the 'mediates cell survival and induction of the iap family of survival proteins' region; 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.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
COMP p.Asp422Gly 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-val591ile (accessed [today's date]).

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