Is COMP p.Gly499Val (c.1496G>T) pathogenic?

COMP p.Gly499Val (c.1496G>T) is classified Uncertain significance in COMP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-11). AlphaMissense: ambiguous (0.4452); Ultra-rare (popmax 0.0516%, amr); Associated with Inborn genetic diseases.

What condition is associated with COMP p.Gly499Val (c.1496G>T)?

COMP p.Gly499Val (c.1496G>T) is associated with Inborn genetic diseases (ClinVar).

How common is COMP p.Gly499Val (c.1496G>T) in the general population?

COMP p.Gly499Val (c.1496G>T) is ultra-rare (popmax 0.0516%, amr) (gnomAD).

What do computational predictors say about COMP p.Gly499Val (c.1496G>T)?

AlphaMissense predicts ambiguous (score 0.4452) — an in-silico prediction, not a clinical call.

COMP p.Gly499Val

c.1496G>T · rs554998204 · VCV1363000

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4452 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0516%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4452	ambiguous
REVEL	0.963	strongly pathogenic-leaning
SaProt	LLR -14.10	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0516% Admixed American · 31/60,036 alleles

Filtering AF 0.0374% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0325%

Overall 0.00217% 35/1,611,590 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0516%	1,937
Remaining individualsnot grpmax-eligible	0.0032%	31,248
European (non-Finnish)	0.000169%	590,016

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.Gly499Val
Coding: c.1496G>T
MANE Select: NM_000095
dbSNP: rs554998204
Type: single nucleotide variant
Location: chr19:18785845 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 499: the 'disordered' 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.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-gly499val (accessed [today's date]).

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