Is COMP p.Ala495Glu (c.1484C>A) pathogenic?

COMP p.Ala495Glu (c.1484C>A) is classified Uncertain significance in COMP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely benign (0.0863); Very rare (popmax 0.00405%, afr); Associated with Inborn genetic diseases.

What condition is associated with COMP p.Ala495Glu (c.1484C>A)?

COMP p.Ala495Glu (c.1484C>A) is associated with Inborn genetic diseases (ClinVar).

How common is COMP p.Ala495Glu (c.1484C>A) in the general population?

COMP p.Ala495Glu (c.1484C>A) is very rare (popmax 0.00405%, afr) (gnomAD).

What do computational predictors say about COMP p.Ala495Glu (c.1484C>A)?

AlphaMissense predicts likely benign (score 0.0863) — an in-silico prediction, not a clinical call.

COMP p.Ala495Glu

c.1484C>A · VCV4232737

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0863 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00405%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0863	likely benign
REVEL	0.46	indeterminate
SaProt	LLR -7.67	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.51	GERP -4
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	1.125	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 0.00405% African / African-American · 3/74,156 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000498%

Overall 0.000187% 3/1,601,946 alleles · very rare

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.Ala495Glu
Coding: c.1484C>A
MANE Select: NM_000095
Type: single nucleotide variant
Location: chr19:18785970 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 495: 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.Ala495Thr Uncertain significance ★ ⚠ same residue
COMP p.Ala495= Likely benign ★ 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

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-ala495glu (accessed [today's date]).

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