Is COMP p.Arg683His (c.2048G>A) pathogenic?

COMP p.Arg683His (c.2048G>A) is classified Uncertain significance in COMP (ClinVar, Single submitter, 1 submitter). AlphaMissense: ambiguous (0.4148); Very rare (popmax 0.00329%, sas); Associated with multiple epiphyseal dysplasia type 1.

What condition is associated with COMP p.Arg683His (c.2048G>A)?

COMP p.Arg683His (c.2048G>A) is associated with multiple epiphyseal dysplasia type 1 (ClinVar).

How common is COMP p.Arg683His (c.2048G>A) in the general population?

COMP p.Arg683His (c.2048G>A) is very rare (popmax 0.00329%, sas) (gnomAD).

How is Multiple epiphyseal dysplasia type 1 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about COMP p.Arg683His (c.2048G>A)?

AlphaMissense predicts ambiguous (score 0.4148) — an in-silico prediction, not a clinical call.

COMP p.Arg683His

c.2048G>A · rs565459602 · VCV1698391

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4148 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

multiple epiphyseal dysplasia type 1

Computational evidence

Protein change
AlphaMissense	0.4148	ambiguous
REVEL	0.925	moderately pathogenic-leaning
SaProt	LLR -13.10	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	32.0	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 0.00329% South Asian · 3/91,084 alleles

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

Overall 0.000929% 15/1,614,068 alleles · very rare exomes 9/1,461,708 · genomes 6/152,360 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,361
Remaining individualsnot grpmax-eligible	0.0016%	62,498
African / African-American	0.00133%	75,068
European (non-Finnish)	0.000847%	118,004

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.Arg683His
Coding: c.2048G>A
MANE Select: NM_000095
dbSNP: rs565459602
Type: single nucleotide variant
Location: chr19:18784230 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 683: the tsp c-terminal domain; the 'mediates cell survival and induction of the iap family of survival proteins' region; a β-strand

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

Disease context

multiple epiphyseal dysplasia type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Multiple epiphyseal dysplasia type 1 (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

COMP p.Arg683Cys Uncertain significance ★ ⚠ same residue
COMP p.Arg683Gly Uncertain significance ★ ⚠ same residue
COMP p.Arg683Leu Uncertain significance ★ ⚠ same residue
COMP p.Arg683Pro Uncertain significance ★ ⚠ same residue
COMP p.Arg718Trp Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asn489Lys Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asn523Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition
COMP p.Asn555Lys 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/comp-p-arg683his (accessed [today's date]).

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