Is COL2A1 p.Ala640Asp (c.1919C>A) pathogenic?

COL2A1 p.Ala640Asp (c.1919C>A) is classified Uncertain significance in COL2A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-13). AlphaMissense: likely pathogenic (0.5748); Absent from gnomAD v4.1.

How common is COL2A1 p.Ala640Asp (c.1919C>A) in the general population?

COL2A1 p.Ala640Asp (c.1919C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about COL2A1 p.Ala640Asp (c.1919C>A)?

AlphaMissense predicts likely pathogenic (score 0.5748) — an in-silico prediction, not a clinical call.

COL2A1 p.Ala640Asp

c.1919C>A · rs1231556901 · VCV2683192

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5748 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5748	likely pathogenic
REVEL	0.517	indeterminate
SaProt	LLR -9.29	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 21 kb · p 2.4e-45 · regional, not allelic
Overall
CADD	25.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: COL2A1
Protein: p.Ala640Asp
Coding: c.1919C>A
MANE Select: NM_001844
dbSNP: rs1231556901
Type: single nucleotide variant
Location: chr12:47984109 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 640: the 'disordered' region; the 'triple-helical region' region

Full COL2A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COL2A1 p.Ala640Val Uncertain significance ★ ⚠ same residue
COL2A1 c.1023+1G>A Pathogenic ★★ same type
COL2A1 c.1024-2A>C Pathogenic ★★ same type
COL2A1 c.1069-2A>G Pathogenic/Likely pathogenic ★★ same type
COL2A1 c.1221+1G>A Pathogenic ★★ same type
COL2A1 c.1222-2A>G Pathogenic ★★ same type
COL2A1 c.1365+1G>A Pathogenic/Likely pathogenic ★★ same type
COL2A1 c.1420-1G>A 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/col2a1-p-ala640asp (accessed [today's date]).

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