Is COL2A1 p.Val359Ala (c.1076T>C) pathogenic?

COL2A1 p.Val359Ala (c.1076T>C) is classified Uncertain significance in COL2A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: likely benign (0.1293); Very rare (popmax 0.000763%, nfe).

How common is COL2A1 p.Val359Ala (c.1076T>C) in the general population?

COL2A1 p.Val359Ala (c.1076T>C) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about COL2A1 p.Val359Ala (c.1076T>C)?

AlphaMissense predicts likely benign (score 0.1293) — an in-silico prediction, not a clinical call.

COL2A1 p.Val359Ala

c.1076T>C · VCV4797606

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1293 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1293	likely benign
REVEL	0.267	benign-leaning
SaProt	LLR -5.53	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 9.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 21 kb · p 2.4e-45 · regional, not allelic
Overall
CADD	19.78	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 0.000763% European (non-Finnish) · 9/1,179,812 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000616% 9/1,460,716 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: COL2A1
Protein: p.Val359Ala
Coding: c.1076T>C
MANE Select: NM_001844
Type: single nucleotide variant
Location: chr12:47989274 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 359: 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.Val359= Conflicting classifications of pathogenicity ★ 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-val359ala (accessed [today's date]).

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