Is COMP p.Pro296Ala (c.886C>G) pathogenic?

COMP p.Pro296Ala (c.886C>G) is classified Uncertain significance in COMP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: ambiguous (0.5001); Very rare (popmax 0.00329%, sas).

How common is COMP p.Pro296Ala (c.886C>G) in the general population?

COMP p.Pro296Ala (c.886C>G) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about COMP p.Pro296Ala (c.886C>G)?

AlphaMissense predicts ambiguous (score 0.5001) — an in-silico prediction, not a clinical call.

COMP p.Pro296Ala

c.886C>G · rs749583854 · VCV2979334

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5001 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5001	ambiguous
REVEL	0.902	moderately pathogenic-leaning
SaProt	LLR -9.36	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	28.5	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 0.00329% South Asian · 3/91,082 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000274% 4/1,459,876 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,361
Remaining individualsnot grpmax-eligible	0.0016%	62,496

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: COMP
Protein: p.Pro296Ala
Coding: c.886C>G
MANE Select: NM_000095
dbSNP: rs749583854
Type: single nucleotide variant
Location: chr19:18788301 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 296: a disulfide bond

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

Similar variants

COMP p.Pro296Arg Likely pathogenic ★ same residue
COMP p.Pro296Leu Conflicting classifications of pathogenicity ★ same residue
COMP p.Pro296Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
COMP p.Arg718Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
COMP p.Asn489Lys Pathogenic/Likely pathogenic ★★ same type
COMP p.Asn523Lys Pathogenic/Likely pathogenic ★★ same type
COMP p.Asn555Lys Pathogenic/Likely pathogenic ★★ same type
COMP p.Asp269Gly 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/comp-p-pro296ala (accessed [today's date]).

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