Is COMP p.Glu632Lys (c.1894G>A) pathogenic?

COMP p.Glu632Lys (c.1894G>A) is classified Uncertain significance in COMP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-09). AlphaMissense: likely benign (0.1972); Ultra-rare (popmax 0.0254%, nfe); Associated with multiple epiphyseal dysplasia type 1.

What condition is associated with COMP p.Glu632Lys (c.1894G>A)?

COMP p.Glu632Lys (c.1894G>A) is associated with multiple epiphyseal dysplasia type 1, pseudoachondroplasia (ClinVar).

How common is COMP p.Glu632Lys (c.1894G>A) in the general population?

COMP p.Glu632Lys (c.1894G>A) is ultra-rare (popmax 0.0254%, nfe) (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.Glu632Lys (c.1894G>A)?

AlphaMissense predicts likely benign (score 0.1972) — an in-silico prediction, not a clinical call.

COMP p.Glu632Lys

c.1894G>A · rs144170209 · VCV889494

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1972 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0254%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple epiphyseal dysplasia type 1

Computational evidence

Protein change
AlphaMissense	0.1972	likely benign
REVEL	0.645	pathogenic-leaning
SaProt	LLR -10.61	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.33 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.1	GERP -3.8, phastCons 0.51
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	24.6	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 0.0254% European (non-Finnish) · 300/1,179,974 alleles

Filtering AF 0.023% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0221%

Overall 0.0203% 327/1,613,740 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.04%	2,499
European (non-Finnish)grpmax	0.0254%	3,933
South Asian	0.0022%	45,538

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Glu632Lys
Coding: c.1894G>A
MANE Select: NM_000095
dbSNP: rs144170209
Type: single nucleotide variant
Location: chr19:18784916 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 632: the tsp c-terminal domain; the 'mediates cell survival and induction of the iap family of survival proteins' region; a disulfide bond

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

Also linked: pseudoachondroplasia

For Multiple epiphyseal dysplasia type 1 (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

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
COMP p.Asp269Gly Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asp273Val Likely pathogenic ★★ same condition
COMP p.Asp326Asn Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asp349His 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-glu632lys (accessed [today's date]).

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