Is COL8A2 p.Pro526Ser (c.1576C>T) pathogenic?

COL8A2 p.Pro526Ser (c.1576C>T) is classified Uncertain significance in COL8A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-29). AlphaMissense: likely benign (0.1574); Ultra-rare (popmax 0.0276%, eas); Associated with Inborn genetic diseases.

What condition is associated with COL8A2 p.Pro526Ser (c.1576C>T)?

COL8A2 p.Pro526Ser (c.1576C>T) is associated with Inborn genetic diseases (ClinVar).

How common is COL8A2 p.Pro526Ser (c.1576C>T) in the general population?

COL8A2 p.Pro526Ser (c.1576C>T) is ultra-rare (popmax 0.0276%, eas) (gnomAD).

What do computational predictors say about COL8A2 p.Pro526Ser (c.1576C>T)?

AlphaMissense predicts likely benign (score 0.1574) — an in-silico prediction, not a clinical call.

COL8A2 p.Pro526Ser

c.1576C>T · rs533259114 · VCV2598926

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1574 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0276%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1574	likely benign
REVEL	0.542	indeterminate
SaProt	LLR -10.68	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 648 bp · p 0.0003 · regional, not allelic
Overall
CADD	24.1	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 0.0276% East Asian · 12/43,434 alleles

Filtering AF 0.0159% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0125%

Overall 0.00159% 24/1,513,694 alleles · ultra-rare exomes 22/1,361,906 · genomes 2/151,788 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0276%	3,620
Ashkenazi Jewishnot grpmax-eligible	0.0121%	8,243
Admixed American	0.0022%	45,516
Remaining individualsnot grpmax-eligible	0.00172%	58,218
South Asian	0.00128%	77,940
European (non-Finnish)	0.000526%	190,110

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.Pro526Ser
Coding: c.1576C>T
MANE Select: NM_005202
dbSNP: rs533259114
Type: single nucleotide variant
Location: chr1:36098105 (GRCh38)
Gene constraint: LOEUF 1.139 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.03
Residue 526: 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.Pro526Thr 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-pro526ser (accessed [today's date]).

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