Is COL11A1 p.Pro735Ala (c.2203C>G) pathogenic?

COL11A1 p.Pro735Ala (c.2203C>G) is classified Conflicting classifications of pathogenicity in COL11A1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-14). AlphaMissense: likely benign (0.1854); Ultra-rare (popmax 0.0167%, amr); Associated with lumbar disk degenerative disorder.

What condition is associated with COL11A1 p.Pro735Ala (c.2203C>G)?

COL11A1 p.Pro735Ala (c.2203C>G) is associated with lumbar disk degenerative disorder, Marshall syndrome, fibrochondrogenesis 1 (ClinVar).

How common is COL11A1 p.Pro735Ala (c.2203C>G) in the general population?

COL11A1 p.Pro735Ala (c.2203C>G) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about COL11A1 p.Pro735Ala (c.2203C>G)?

AlphaMissense predicts likely benign (score 0.1854) — an in-silico prediction, not a clinical call.

COL11A1 p.Pro735Ala

c.2203C>G · rs752066122 · VCV1961384

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1854 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lumbar disk degenerative disorder

Computational evidence

Protein change
AlphaMissense	0.1854	likely benign
REVEL	0.759	pathogenic-leaning
SaProt	LLR -9.04	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 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 230 kb · p 0.038 · regional, not allelic
Overall
CADD	27.7	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 0.0167% Admixed American · 10/59,880 alleles

Filtering AF 0.00901% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00683%

Overall 0.000621% 10/1,611,464 alleles · ultra-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: COL11A1
Protein: p.Pro735Ala
Coding: c.2203C>G
MANE Select: NM_001854
dbSNP: rs752066122
Type: single nucleotide variant
Location: chr1:102997118 (GRCh38)
Gene constraint: LOEUF 0.349 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 53.06
Residue 735: the 'disordered' region; the 'triple-helical region' region

Full COL11A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

lumbar disk degenerative disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Marshall syndrome fibrochondrogenesis 1 Stickler syndrome type 2 hearing loss, autosomal dominant 37

Similar variants

COL11A1 p.Pro735Leu Uncertain significance ★ ⚠ same residue
COL11A1 c.1245+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL11A1 c.1245+1G>T Pathogenic/Likely pathogenic ★★ same condition
COL11A1 c.2241+5G>T Pathogenic/Likely pathogenic ★★ same condition
COL11A1 c.2808+1G>A Pathogenic ★★ same condition
COL11A1 c.2916+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL11A1 c.3168+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL11A1 c.3762+2T>C Pathogenic/Likely pathogenic ★★ 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/col11a1-p-pro735ala (accessed [today's date]).

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