Is COMP p.Val128Ile (c.382G>A) pathogenic?

COMP p.Val128Ile (c.382G>A) is classified Conflicting classifications of pathogenicity in COMP (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-06). AlphaMissense: likely benign (0.0563); Ultra-rare (popmax 0.0384%, nfe); Associated with connective tissue disorder.

What condition is associated with COMP p.Val128Ile (c.382G>A)?

COMP p.Val128Ile (c.382G>A) is associated with connective tissue disorder (ClinVar).

How common is COMP p.Val128Ile (c.382G>A) in the general population?

COMP p.Val128Ile (c.382G>A) is ultra-rare (popmax 0.0384%, nfe) (gnomAD).

What do computational predictors say about COMP p.Val128Ile (c.382G>A)?

AlphaMissense predicts likely benign (score 0.0563) — an in-silico prediction, not a clinical call.

COMP p.Val128Ile

c.382G>A · rs143954978 · VCV1540004

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0563 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0384%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

connective tissue disorder

Computational evidence

Protein change
AlphaMissense	0.0563	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -6.03	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 -0.45	GERP -3.7, phastCons 0.071
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	15.91	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 0.0384% European (non-Finnish) · 452/1,177,602 alleles

Filtering AF 0.0354% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0342%

Overall 0.0297% 473/1,592,262 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0384%	2,605
Remaining individualsnot grpmax-eligible	0.021%	4,753
African / African-American	0.00669%	14,946
Finnishnot grpmax-eligible	0.00402%	24,849
Admixed American	0.00169%	59,010

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.Val128Ile
Coding: c.382G>A
MANE Select: NM_000095
dbSNP: rs143954978
Type: single nucleotide variant
Location: chr19:18789950 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 128: the egf-like 2; calcium-binding domain

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

Disease context

connective tissue disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COMP c.217+4A>G Uncertain significance ★★ same condition
COMP p.Ser444Cys Uncertain significance ★★ ⚠ same condition
COMP c.2227+8G>A Benign/Likely benign ★★ same condition
COMP p.Ala171Thr Benign/Likely benign ★★ same condition
COMP p.Arg718= Benign/Likely benign ★★ same condition
COMP p.Asn386Asp Benign/Likely benign ★★ same condition
COMP p.Asn652= Benign/Likely benign ★★ same condition
COMP p.Phe137Ser Benign/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/comp-p-val128ile (accessed [today's date]).

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