Is COMP p.Gln756Arg (c.2267A>G) pathogenic?

COMP p.Gln756Arg (c.2267A>G) is classified Benign/Likely benign in COMP (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-05-09). AlphaMissense: likely benign (0.0613); Common (popmax 20.6%, afr) — too common for a highly-penetrant pathogenic allele; Associated with pseudoachondroplasia.

What condition is associated with COMP p.Gln756Arg (c.2267A>G)?

COMP p.Gln756Arg (c.2267A>G) is associated with pseudoachondroplasia, multiple epiphyseal dysplasia type 1 (ClinVar).

How is Pseudoachondroplasia inherited?

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

What do computational predictors say about COMP p.Gln756Arg (c.2267A>G)?

AlphaMissense predicts likely benign (score 0.0613) — an in-silico prediction, not a clinical call.

COMP p.Gln756Arg

Q: How common is COMP p.Gln756Arg (c.2267A>G) in the general population?

COMP p.Gln756Arg (c.2267A>G) is common (popmax 20.6%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2267A>G · rs61752496 · VCV255124

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0613 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 20.6%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pseudoachondroplasia

Computational evidence

Protein change
AlphaMissense	0.0613	likely benign
REVEL	0.15	moderately benign-leaning
SaProt	LLR -4.69	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.23	GERP -2.8
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	6.86	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 20.6% African / African-American · 15,410/74,920 alleles

Filtering AF 20.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 20.2%

Overall 1.2% 19,283/1,611,810 alleles · common exomes 10,414/1,459,632 · genomes 8,869/152,178 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	20.6%	5
Remaining individualsnot grpmax-eligible	1.66%	60
Middle Eastern	1.36%	73
Admixed American	1.34%	75
Ashkenazi Jewishnot grpmax-eligible	1.34%	75
South Asian	1.17%	85
European (non-Finnish)	0.0417%	2,398
East Asian	0.00892%	11,216

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.Gln756Arg
Coding: c.2267A>G
MANE Select: NM_000095
dbSNP: rs61752496
Type: single nucleotide variant
Location: chr19:18782922 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 756: a UniProt-annotated variant site (in a patient with multiple epiphyseal dysplasia); the 'mediates cell survival and induction of the iap family of survival proteins' region

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

Disease context

pseudoachondroplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: multiple epiphyseal dysplasia type 1

For Pseudoachondroplasia (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

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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-gln756arg (accessed [today's date]).

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