Is COL11A2 p.Pro445Ala (c.1333C>G) pathogenic?

COL11A2 p.Pro445Ala (c.1333C>G) is classified Uncertain significance in COL11A2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-30). AlphaMissense: likely benign (0.0867); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with COL11A2 p.Pro445Ala (c.1333C>G)?

COL11A2 p.Pro445Ala (c.1333C>G) is associated with Inborn genetic diseases (ClinVar).

How common is COL11A2 p.Pro445Ala (c.1333C>G) in the general population?

COL11A2 p.Pro445Ala (c.1333C>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about COL11A2 p.Pro445Ala (c.1333C>G)?

AlphaMissense predicts likely benign (score 0.0867) — an in-silico prediction, not a clinical call.

COL11A2 p.Pro445Ala

c.1333C>G · rs1261759387 · VCV1488922

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0867 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0867	likely benign
REVEL	0.768	pathogenic-leaning
SaProt	LLR -7.04	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 29 kb · p 3e-20 · 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

Grpmax group 0.0011% South Asian · 1/91,084 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,612,888 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,084
European (non-Finnish)	0.000169%	590,019

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.Pro445Ala
Coding: c.1333C>G
MANE Select: NM_080680
dbSNP: rs1261759387
Type: single nucleotide variant
Location: chr6:33180284 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.18
Residue 445: the 'nonhelical region' region; the 'disordered' region; the collagen-like 1 domain

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.Pro445Ser Uncertain significance ★★ ⚠ same residue
COL11A2 p.Pro445Arg Uncertain significance ★ ⚠ same residue
COL11A2 p.Pro445= Likely 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

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-pro445ala (accessed [today's date]).

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