Is COL22A1 p.Trp14Cys (c.42G>T) pathogenic?

COL22A1 p.Trp14Cys (c.42G>T) is classified Uncertain significance in COL22A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-24). AlphaMissense: likely benign (0.1896); Ultra-rare (popmax 0.0165%, mid).

How common is COL22A1 p.Trp14Cys (c.42G>T) in the general population?

COL22A1 p.Trp14Cys (c.42G>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about COL22A1 p.Trp14Cys (c.42G>T)?

AlphaMissense predicts likely benign (score 0.1896) — an in-silico prediction, not a clinical call.

COL22A1 p.Trp14Cys

c.42G>T · rs1364245161 · VCV3147445

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1896 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1896	likely benign
REVEL	0.305	indeterminate
SaProt	LLR -6.92	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 0.56	GERP 1.8, phastCons 0.017
Regional constraint	o/e 1.03	unconstrained · MANE · 294 kb · p 0.19 · regional, not allelic
Overall
CADD	18.9	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 0.0165% Middle Eastern · 1/6,050 alleles

Overall 6.92e-05% 1/1,445,464 alleles · ultra-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: COL22A1
Protein: p.Trp14Cys
Coding: c.42G>T
MANE Select: NM_152888
dbSNP: rs1364245161
Type: single nucleotide variant
Location: chr8:138883131 (GRCh38)
Gene constraint: LOEUF 1.005 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.25

Full COL22A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COL22A1 p.Glu736Asp Benign ★★ same type
COL22A1 p.Gly1180= Benign ★★ same type
COL22A1 p.Pro763Leu Benign ★★ same type
COL22A1 p.Ala1005Ser Uncertain significance ★ ⚠ same type
COL22A1 p.Ala103Val Uncertain significance ★ ⚠ same type
COL22A1 p.Ala1077Gly Uncertain significance ★ ⚠ same type
COL22A1 p.Ala120Ser Uncertain significance ★ ⚠ same type
COL22A1 p.Ala1212Ser Uncertain significance ★ ⚠ 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/col22a1-p-trp14cys (accessed [today's date]).

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