Is COL22A1 p.Phe90Ser (c.269T>C) pathogenic?

COL22A1 p.Phe90Ser (c.269T>C) is classified Uncertain significance in COL22A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-21). AlphaMissense: likely pathogenic (0.9821); Very rare (popmax 0.00017%, nfe).

How common is COL22A1 p.Phe90Ser (c.269T>C) in the general population?

COL22A1 p.Phe90Ser (c.269T>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about COL22A1 p.Phe90Ser (c.269T>C)?

AlphaMissense predicts likely pathogenic (score 0.9821) — an in-silico prediction, not a clinical call.

COL22A1 p.Phe90Ser

c.269T>C · VCV4655558

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9821 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9821	likely pathogenic · top 2% in COL22A1
REVEL	0.828	moderately pathogenic-leaning
SaProt	LLR -11.81	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 9	GERP 1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 294 kb · p 0.19 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00017% European (non-Finnish) · 2/1,177,094 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000125% 2/1,606,100 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: COL22A1
Protein: p.Phe90Ser
Coding: c.269T>C
MANE Select: NM_152888
Type: single nucleotide variant
Location: chr8:138878139 (GRCh38)
Gene constraint: LOEUF 1.005 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.25
Residue 90: the vwfa domain

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-phe90ser (accessed [today's date]).

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