Is COMP p.Ile198Phe (c.592A>T) pathogenic?

COMP p.Ile198Phe (c.592A>T) is classified Uncertain significance in COMP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-27). AlphaMissense: likely benign (0.0899); Very rare (popmax 0.00167%, amr).

How common is COMP p.Ile198Phe (c.592A>T) in the general population?

COMP p.Ile198Phe (c.592A>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about COMP p.Ile198Phe (c.592A>T)?

AlphaMissense predicts likely benign (score 0.0899) — an in-silico prediction, not a clinical call.

COMP p.Ile198Phe

c.592A>T · rs1424892887 · VCV1348472

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0899 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0899	likely benign
REVEL	0.178	moderately benign-leaning
SaProt	LLR -8.34	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 -0.76	GERP -1, phastCons 0.013
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	17.47	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,010 alleles

Overall 0.000137% 2/1,461,602 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,010
European (non-Finnish)	8.47e-05%	1,179,979

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.Ile198Phe
Coding: c.592A>T
MANE Select: NM_000095
dbSNP: rs1424892887
Type: single nucleotide variant
Location: chr19:18788850 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 198: a disulfide bond; the egf-like 3; calcium-binding domain

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

Similar variants

COMP p.Ile198= Likely benign ★★ same residue
COMP p.Arg718Trp Pathogenic/Likely pathogenic ★★ same type
COMP p.Asn489Lys Pathogenic/Likely pathogenic ★★ same type
COMP p.Asn523Lys Pathogenic/Likely pathogenic ★★ ⚠ same type
COMP p.Asn555Lys Pathogenic/Likely pathogenic ★★ same type
COMP p.Asp269Gly Pathogenic/Likely pathogenic ★★ same type
COMP p.Asp273Val Likely pathogenic ★★ same type
COMP p.Asp326Asn Pathogenic/Likely pathogenic ★★ same type

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-ile198phe (accessed [today's date]).

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