Is COL2A1 p.Ala377= (c.1131C>T) pathogenic?

COL2A1 p.Ala377= (c.1131C>T) is classified Likely benign in COL2A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-31). Very rare (popmax 0.00663%, sas).

How common is COL2A1 p.Ala377= (c.1131C>T) in the general population?

COL2A1 p.Ala377= (c.1131C>T) is very rare (popmax 0.00663%, sas) (gnomAD).

COL2A1 p.Ala377=

c.1131C>T · rs376615403 · VCV2066944

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00663%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.76	GERP -3.5
Overall
CADD	10.79	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00663% South Asian · 6/90,450 alleles

Filtering AF 0.00512% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00469%

Overall 0.00509% 82/1,610,986 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00663%	15,075
European (non-Finnish)	0.00628%	15,925
Remaining individualsnot grpmax-eligible	0.0016%	62,324
Finnishnot grpmax-eligible	0.00157%	63,834

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.Ala377=
Coding: c.1131C>T
MANE Select: NM_001844
dbSNP: rs376615403
Type: single nucleotide variant
Location: chr12:47987701 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 377: 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.Ala377Thr Pathogenic ★ ⚠ same residue
COL2A1 p.Ala377Ser 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

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-ala377 (accessed [today's date]).

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