Is COL8A2 p.Pro321Thr (c.961C>A) pathogenic?

COL8A2 p.Pro321Thr (c.961C>A) is classified Uncertain significance in COL8A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-20). AlphaMissense: likely benign (0.0942); Ultra-rare (popmax 0.0179%, eas); Associated with Inborn genetic diseases.

What condition is associated with COL8A2 p.Pro321Thr (c.961C>A)?

COL8A2 p.Pro321Thr (c.961C>A) is associated with Inborn genetic diseases (ClinVar).

How common is COL8A2 p.Pro321Thr (c.961C>A) in the general population?

COL8A2 p.Pro321Thr (c.961C>A) is ultra-rare (popmax 0.0179%, eas) (gnomAD).

What do computational predictors say about COL8A2 p.Pro321Thr (c.961C>A)?

AlphaMissense predicts likely benign (score 0.0942) — an in-silico prediction, not a clinical call.

COL8A2 p.Pro321Thr

c.961C>A · VCV3268870

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0942 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0179%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0942	likely benign
REVEL	0.411	indeterminate
SaProt	LLR -9.38	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 1,954 bp · p 0.078 · regional, not allelic
Overall
CADD	21.9	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 0.0179% East Asian · 8/44,808 alleles

Filtering AF 0.00885% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00642%

Overall 0.000559% 9/1,610,410 alleles · ultra-rare exomes 9/1,458,310 · genomes 0/152,100 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0179%	5,601
Remaining individualsnot grpmax-eligible	0.0016%	62,362

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: COL8A2
Protein: p.Pro321Thr
Coding: c.961C>A
MANE Select: NM_005202
Type: single nucleotide variant
Location: chr1:36098720 (GRCh38)
Gene constraint: LOEUF 1.139 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.03
Residue 321: the 'disordered' region; the 'triple-helical region' region

Full COL8A2 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

COL8A2 p.Arg149Gln Uncertain significance ★★ ⚠ same condition
COL8A2 p.Arg263Ser Uncertain significance ★★ ⚠ same condition
COL8A2 p.Arg372Cys Uncertain significance ★★ ⚠ same condition
COL8A2 p.Glu568Lys Uncertain significance ★★ ⚠ same condition
COL8A2 p.Gly549Ser Uncertain significance ★★ ⚠ same condition
COL8A2 p.Gly550Ser Uncertain significance ★★ ⚠ same condition
COL8A2 p.Gly559Glu Uncertain significance ★★ ⚠ same condition
COL8A2 p.Gly601Ala 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/col8a2-p-pro321thr (accessed [today's date]).

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