Is COMP p.Arg247Ser (c.739C>A) pathogenic?

COMP p.Arg247Ser (c.739C>A) is classified Uncertain significance in COMP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-14). AlphaMissense: likely pathogenic (0.6153); Ultra-rare (popmax 0.0835%, mid); Associated with Inborn genetic diseases.

What condition is associated with COMP p.Arg247Ser (c.739C>A)?

COMP p.Arg247Ser (c.739C>A) is associated with Inborn genetic diseases (ClinVar).

How common is COMP p.Arg247Ser (c.739C>A) in the general population?

COMP p.Arg247Ser (c.739C>A) is ultra-rare (popmax 0.0835%, mid) (gnomAD).

What do computational predictors say about COMP p.Arg247Ser (c.739C>A)?

AlphaMissense predicts likely pathogenic (score 0.6153) — an in-silico prediction, not a clinical call.

COMP p.Arg247Ser

c.739C>A · rs537695502 · VCV2956892

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6153 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0835%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6153	likely pathogenic
REVEL	0.517	indeterminate
SaProt	LLR -4.69	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	26.2	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 0.0835% Middle Eastern · 5/5,990 alleles

Filtering AF 0.0328% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0213%

Overall 0.000645% 10/1,549,852 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0835%	1,198
European (non-Finnish)	0.000436%	229,482

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.Arg247Ser
Coding: c.739C>A
MANE Select: NM_000095
dbSNP: rs537695502
Type: single nucleotide variant
Location: chr19:18788615 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 247: a disulfide bond; the egf-like 4 domain

Full COMP 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

COMP p.Arg352Trp Uncertain significance ★★ ⚠ same condition
COMP p.Arg379Gln Uncertain significance ★★ ⚠ same condition
COMP p.Arg381Leu Uncertain significance ★★ ⚠ same condition
COMP p.Arg665Trp Uncertain significance ★★ ⚠ same condition
COMP p.Arg689Trp Uncertain significance ★★ ⚠ same condition
COMP p.Arg721His Uncertain significance ★★ ⚠ same condition
COMP p.Asp422Gly Uncertain significance ★★ ⚠ same condition
COMP p.Asp507Asn 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/comp-p-arg247ser (accessed [today's date]).

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