Is COMP p.Ala653Thr (c.1957G>A) pathogenic?

COMP p.Ala653Thr (c.1957G>A) is classified Uncertain significance in COMP (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). AlphaMissense: likely pathogenic (0.7082); Very rare (popmax 0.00483%, nfe).

How common is COMP p.Ala653Thr (c.1957G>A) in the general population?

COMP p.Ala653Thr (c.1957G>A) is very rare (popmax 0.00483%, nfe) (gnomAD).

What do computational predictors say about COMP p.Ala653Thr (c.1957G>A)?

AlphaMissense predicts likely pathogenic (score 0.7082) — an in-silico prediction, not a clinical call.

COMP p.Ala653Thr

c.1957G>A · rs1416152202 · VCV1511790

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7082 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00483%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7082	likely pathogenic
REVEL	0.697	pathogenic-leaning
SaProt	LLR -9.98	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP -0.49, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	23.5	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 0.00483% European (non-Finnish) · 57/1,180,044 alleles

Filtering AF 0.00377% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00345%

Overall 0.00384% 62/1,613,958 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00483%	20,703
Remaining individualsnot grpmax-eligible	0.0048%	20,829
East Asian	0.00223%	44,898
African / African-American	0.00133%	74,914

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.Ala653Thr
Coding: c.1957G>A
MANE Select: NM_000095
dbSNP: rs1416152202
Type: single nucleotide variant
Location: chr19:18784321 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 653: the tsp c-terminal domain; the 'mediates cell survival and induction of the iap family of survival proteins' region; an α-helix; a disulfide bond

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

Similar variants

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
COMP p.Asp349His 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-ala653thr (accessed [today's date]).

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