Is COMP p.Gln164His (c.492G>C) pathogenic?

COMP p.Gln164His (c.492G>C) is classified Uncertain significance in COMP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-18). AlphaMissense: likely benign (0.1467); Very rare (popmax 0.00204%, amr).

How common is COMP p.Gln164His (c.492G>C) in the general population?

COMP p.Gln164His (c.492G>C) is very rare (popmax 0.00204%, amr) (gnomAD).

What do computational predictors say about COMP p.Gln164His (c.492G>C)?

AlphaMissense predicts likely benign (score 0.1467) — an in-silico prediction, not a clinical call.

COMP p.Gln164His

c.492G>C · VCV3615808

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1467 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00204%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1467	likely benign
REVEL	0.387	indeterminate
SaProt	LLR -7.25	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.02	GERP -0.55, phastCons 0.58
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	19.99	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 0.00204% Admixed American · 1/49,006 alleles

Overall 7.08e-05% 1/1,412,754 alleles · very rare

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.Gln164His
Coding: c.492G>C
MANE Select: NM_000095
Type: single nucleotide variant
Location: chr19:18789196 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 164: the egf-like 2; calcium-binding domain; a disulfide bond

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

Similar variants

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
COMP p.Asp349His 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-gln164his (accessed [today's date]).

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