Is COL8A2 p.Arg25Trp (c.73C>T) pathogenic?

COL8A2 p.Arg25Trp (c.73C>T) is classified Uncertain significance in COL8A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely benign (0.139); Ultra-rare (popmax 0.0496%, mid); Associated with Inborn genetic diseases.

What condition is associated with COL8A2 p.Arg25Trp (c.73C>T)?

COL8A2 p.Arg25Trp (c.73C>T) is associated with Inborn genetic diseases (ClinVar).

How common is COL8A2 p.Arg25Trp (c.73C>T) in the general population?

COL8A2 p.Arg25Trp (c.73C>T) is ultra-rare (popmax 0.0496%, mid) (gnomAD).

What do computational predictors say about COL8A2 p.Arg25Trp (c.73C>T)?

AlphaMissense predicts likely benign (score 0.139) — an in-silico prediction, not a clinical call.

COL8A2 p.Arg25Trp

c.73C>T · rs546556937 · VCV3147827

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.139 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0496%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.139	likely benign
REVEL	0.22	benign-leaning
SaProt	LLR -7.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.46	GERP -3.2
Regional constraint	o/e 0.93	unconstrained · MANE · 1,954 bp · p 0.078 · regional, not allelic
Overall
CADD	18.76	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 0.0496% Middle Eastern · 3/6,046 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0072%

Overall 0.00739% 119/1,610,560 alleles · ultra-rare exomes 109/1,458,280 · genomes 10/152,280 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0496%	2,015
South Asian	0.0132%	7,562
Remaining individualsnot grpmax-eligible	0.00802%	12,462
European (non-Finnish)	0.00763%	13,098
Admixed American	0.00503%	19,895
East Asian	0.00446%	22,401
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,500
African / African-American	0.00267%	37,503
Finnishnot grpmax-eligible	0.00159%	62,752

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.Arg25Trp
Coding: c.73C>T
MANE Select: NM_005202
dbSNP: rs546556937
Type: single nucleotide variant
Location: chr1:36100170 (GRCh38)
Gene constraint: LOEUF 1.139 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.03

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.Arg25Gln Uncertain significance ★ ⚠ same residue
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

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-arg25trp (accessed [today's date]).

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