Is COMP p.Thr119Met (c.356C>T) pathogenic?

COMP p.Thr119Met (c.356C>T) is classified Uncertain significance in COMP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-01). AlphaMissense: likely benign (0.0937); Very rare (popmax 0.00673%, amr).

How common is COMP p.Thr119Met (c.356C>T) in the general population?

COMP p.Thr119Met (c.356C>T) is very rare (popmax 0.00673%, amr) (gnomAD).

What do computational predictors say about COMP p.Thr119Met (c.356C>T)?

AlphaMissense predicts likely benign (score 0.0937) — an in-silico prediction, not a clinical call.

COMP p.Thr119Met

c.356C>T · rs1292218782 · VCV1921350

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0937 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00673%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0937	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -7.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4	GERP -3.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	24.8	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 0.00673% Admixed American · 4/59,476 alleles

Filtering AF 0.00227% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000501% 8/1,595,314 alleles · very rare exomes 6/1,443,312 · genomes 2/152,002 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00673%	14,869
African / African-American	0.00401%	24,923
European (non-Finnish)	8.49e-05%	1,178,178

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.Thr119Met
Coding: c.356C>T
MANE Select: NM_000095
dbSNP: rs1292218782
Type: single nucleotide variant
Location: chr19:18789976 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 119: the egf-like 1 domain

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

Similar variants

COMP p.Thr119= Likely benign ★ same residue
COMP p.Arg718Trp Pathogenic/Likely pathogenic ★★ same type
COMP p.Asn489Lys Pathogenic/Likely pathogenic ★★ same type
COMP p.Asn523Lys Pathogenic/Likely pathogenic ★★ ⚠ same type
COMP p.Asn555Lys Pathogenic/Likely pathogenic ★★ same type
COMP p.Asp269Gly Pathogenic/Likely pathogenic ★★ same type
COMP p.Asp273Val Likely pathogenic ★★ same type
COMP p.Asp326Asn Pathogenic/Likely pathogenic ★★ same type

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-thr119met (accessed [today's date]).

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