Is COMP p.Asp518His (c.1552G>C) pathogenic?

COMP p.Asp518His (c.1552G>C) is classified Pathogenic/Likely pathogenic in COMP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-21). AlphaMissense: likely pathogenic (0.9916); Absent from gnomAD v4.1; Associated with COMP-related disorder.

What condition is associated with COMP p.Asp518His (c.1552G>C)?

COMP p.Asp518His (c.1552G>C) is associated with COMP-related disorder, pseudoachondroplasia (ClinVar).

How common is COMP p.Asp518His (c.1552G>C) in the general population?

COMP p.Asp518His (c.1552G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about COMP p.Asp518His (c.1552G>C)?

AlphaMissense predicts likely pathogenic (score 0.9916) — an in-silico prediction, not a clinical call.

COMP p.Asp518His

c.1552G>C · rs1359984033 · VCV803547

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9916 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

COMP-related disorder

Computational evidence

Protein change
AlphaMissense	0.9916	likely pathogenic ✓ concordant with ClinVar · top 8% in COMP
REVEL	0.978	strongly pathogenic-leaning
SaProt	LLR -17.28	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	33.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: COMP
Protein: p.Asp518His
Coding: c.1552G>C
MANE Select: NM_000095
dbSNP: rs1359984033
Type: single nucleotide variant
Location: chr19:18785789 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 518: a UniProt-annotated variant site (in psach; mild form)

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

Disease context

COMP-related disorder

Also linked: pseudoachondroplasia

Similar variants

COMP p.Asp518Asn Pathogenic ★ same residue
COMP p.Asp518Gly Pathogenic ★ same residue
COMP p.Asn489Lys 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
COMP p.Asp385Asn 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-asp518his (accessed [today's date]).

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