Is COL8A2 p.Pro54Leu (c.161C>T) pathogenic?

COL8A2 p.Pro54Leu (c.161C>T) is classified Likely benign in COL8A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-16). AlphaMissense: likely benign (0.3397); Ultra-rare (popmax 0.0334%, amr).

How common is COL8A2 p.Pro54Leu (c.161C>T) in the general population?

COL8A2 p.Pro54Leu (c.161C>T) is ultra-rare (popmax 0.0334%, amr) (gnomAD).

What do computational predictors say about COL8A2 p.Pro54Leu (c.161C>T)?

AlphaMissense predicts likely benign (score 0.3397) — an in-silico prediction, not a clinical call.

COL8A2 p.Pro54Leu

c.161C>T · VCV3910086

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3397 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.3397	likely benign
REVEL	0.495	indeterminate
SaProt	LLR -6.57	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 1,954 bp · p 0.078 · regional, not allelic
Overall
CADD	26.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0334% Admixed American · 20/59,942 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.00267% 43/1,611,686 alleles · ultra-rare exomes 29/1,459,516 · genomes 14/152,170 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0334%	2,997
East Asian	0.00223%	44,802
European (non-Finnish)	0.0017%	58,915
Finnishnot grpmax-eligible	0.00157%	63,822
South Asian	0.0011%	91,060

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.Pro54Leu
Coding: c.161C>T
MANE Select: NM_005202
Type: single nucleotide variant
Location: chr1:36100082 (GRCh38)
Gene constraint: LOEUF 1.139 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.03
Residue 54: the 'nonhelical region (nc2)' region

Full COL8A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COL8A2 p.Arg149Gln Uncertain significance ★★ ⚠ same type
COL8A2 p.Arg263Ser Uncertain significance ★★ ⚠ same type
COL8A2 p.Arg372Cys Uncertain significance ★★ ⚠ same type
COL8A2 p.Glu568Lys Uncertain significance ★★ ⚠ same type
COL8A2 p.Gly549Ser Uncertain significance ★★ ⚠ same type
COL8A2 p.Gly550Ser Uncertain significance ★★ ⚠ same type
COL8A2 p.Gly559Glu Uncertain significance ★★ ⚠ same type
COL8A2 p.Gly601Ala 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/col8a2-p-pro54leu (accessed [today's date]).

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