Is COMP p.Asp399Val (c.1196A>T) pathogenic?

COMP p.Asp399Val (c.1196A>T) is classified Conflicting classifications of pathogenicity in COMP (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-08-04). AlphaMissense: likely pathogenic (0.9876); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with COMP p.Asp399Val (c.1196A>T)?

COMP p.Asp399Val (c.1196A>T) is associated with Inborn genetic diseases (ClinVar).

How common is COMP p.Asp399Val (c.1196A>T) in the general population?

COMP p.Asp399Val (c.1196A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about COMP p.Asp399Val (c.1196A>T)?

AlphaMissense predicts likely pathogenic (score 0.9876) — an in-silico prediction, not a clinical call.

COMP p.Asp399Val

c.1196A>T · rs2145901343 · VCV1522000

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9876 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9876	likely pathogenic
REVEL	0.894	moderately pathogenic-leaning
SaProt	LLR -18.66	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 7.8	GERP 2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	29.9	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.Asp399Val
Coding: c.1196A>T
MANE Select: NM_000095
dbSNP: rs2145901343
Type: single nucleotide variant
Location: chr19:18786590 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 399: the 'disordered' region; a disulfide bond

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.Asp399Tyr Likely pathogenic ★ same residue
COMP p.Asp399Asn Likely pathogenic ★★ same residue
COMP p.Asp399His Uncertain significance ★ same residue
COMP p.Arg247Ser Uncertain significance ★★ ⚠ same condition
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

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-asp399val (accessed [today's date]).

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