Is COL11A2 p.Pro599Ser (c.1795C>T) pathogenic?

COL11A2 p.Pro599Ser (c.1795C>T) is classified Uncertain significance in COL11A2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-16). AlphaMissense: likely benign (0.1409); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with COL11A2 p.Pro599Ser (c.1795C>T)?

COL11A2 p.Pro599Ser (c.1795C>T) is associated with Inborn genetic diseases (ClinVar).

How common is COL11A2 p.Pro599Ser (c.1795C>T) in the general population?

COL11A2 p.Pro599Ser (c.1795C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about COL11A2 p.Pro599Ser (c.1795C>T)?

AlphaMissense predicts likely benign (score 0.1409) — an in-silico prediction, not a clinical call.

COL11A2 p.Pro599Ser

c.1795C>T · rs2535196052 · VCV2318165

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1409 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1409	likely benign
REVEL	0.657	pathogenic-leaning
SaProt	LLR -9.07	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.7	GERP 0.63, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 29 kb · p 3e-20 · regional, not allelic
Overall
CADD	26.0	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 8.48e-05% European (non-Finnish) · 1/1,179,852 alleles

Overall 6.2e-05% 1/1,612,632 alleles · very rare exomes 1/1,460,782 · genomes 0/151,850 · joint denominator

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.Pro599Ser
Coding: c.1795C>T
MANE Select: NM_080680
dbSNP: rs2535196052
Type: single nucleotide variant
Location: chr6:33178331 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.18
Residue 599: the 'disordered' region; the 'triple-helical 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.Pro599Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
COL11A2 p.Pro599Arg Uncertain significance ★ ⚠ 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-pro599ser (accessed [today's date]).

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