Is COL11A2 p.Ala476Val (c.1427C>T) pathogenic?

COL11A2 p.Ala476Val (c.1427C>T) is classified Conflicting classifications of pathogenicity in COL11A2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-05-13). AlphaMissense: ambiguous (0.4224); Ultra-rare (popmax 0.0801%, sas); Associated with Inborn genetic diseases.

What condition is associated with COL11A2 p.Ala476Val (c.1427C>T)?

COL11A2 p.Ala476Val (c.1427C>T) is associated with Inborn genetic diseases (ClinVar).

How common is COL11A2 p.Ala476Val (c.1427C>T) in the general population?

COL11A2 p.Ala476Val (c.1427C>T) is ultra-rare (popmax 0.0801%, sas) (gnomAD).

What do computational predictors say about COL11A2 p.Ala476Val (c.1427C>T)?

AlphaMissense predicts ambiguous (score 0.4224) — an in-silico prediction, not a clinical call.

COL11A2 p.Ala476Val

c.1427C>T · rs373983482 · VCV179347

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4224 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0801%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4224	ambiguous
REVEL	0.707	pathogenic-leaning
SaProt	LLR -7.63	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 29 kb · p 3e-20 · regional, not allelic
Overall
CADD	32.0	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 0.0801% South Asian · 73/91,084 alleles

Filtering AF 0.0654% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0599%

Overall 0.00546% 88/1,611,866 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0801%	1,248
Remaining individualsnot grpmax-eligible	0.0048%	20,824
East Asian	0.00223%	44,880
Admixed American	0.00167%	59,998
Finnishnot grpmax-eligible	0.00161%	61,978
African / African-American	0.00134%	74,868
European (non-Finnish)	0.000678%	147,498

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: COL11A2
Protein: p.Ala476Val
Coding: c.1427C>T
MANE Select: NM_080680
dbSNP: rs373983482
Type: single nucleotide variant
Location: chr6:33179738 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.18
Residue 476: the 'nonhelical region' region

Full COL11A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COL11A2 p.Ala476Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
COL11A2 p.Ala476= Benign ★ same residue
COL11A2 p.Ala216Glu Uncertain significance ★★ ⚠ same condition
COL11A2 p.Ala66Pro Uncertain significance ★★ ⚠ same condition
COL11A2 p.Ala827Gly Uncertain significance ★★ ⚠ same condition
COL11A2 p.Arg1596Gln Uncertain significance ★★ ⚠ same condition
COL11A2 p.Arg1667Ser Uncertain significance ★★ ⚠ same condition
COL11A2 p.Arg36Gln Uncertain significance ★★ ⚠ same condition

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/col11a2-p-ala476val (accessed [today's date]).

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