Is COL8A2 p.Pro575Leu (c.1724C>T) pathogenic?

COL8A2 p.Pro575Leu (c.1724C>T) is classified Benign in COL8A2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-12). AlphaMissense: likely pathogenic (0.7453); Rare (popmax 0.108%, nfe).

How common is COL8A2 p.Pro575Leu (c.1724C>T) in the general population?

COL8A2 p.Pro575Leu (c.1724C>T) is rare (popmax 0.108%, nfe) (gnomAD).

What do computational predictors say about COL8A2 p.Pro575Leu (c.1724C>T)?

AlphaMissense predicts likely pathogenic (score 0.7453) — an in-silico prediction, not a clinical call.

COL8A2 p.Pro575Leu

c.1724C>T · rs145553904 · VCV1536255

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7453 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.108%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7453	likely pathogenic
REVEL	0.719	pathogenic-leaning
SaProt	LLR -8.57	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 648 bp · p 0.0003 · regional, not allelic
Overall
CADD	24.9	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 0.108% European (non-Finnish) · 1,268/1,178,990 alleles

Filtering AF 0.103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.101%

Overall 0.101% 1,618/1,608,466 alleles · rare exomes 1,405/1,456,146 · genomes 213/152,320 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.43%	70
Finnishnot grpmax-eligible	0.407%	246
Remaining individualsnot grpmax-eligible	0.111%	904
European (non-Finnish)grpmax	0.108%	930
Admixed American	0.0218%	4,586
Ashkenazi Jewishnot grpmax-eligible	0.0102%	9,843
African / African-American	0.00533%	18,758
East Asian	0.00446%	22,401
South Asian	0.0011%	90,908

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro575Leu
Coding: c.1724C>T
MANE Select: NM_005202
dbSNP: rs145553904
Type: single nucleotide variant
Location: chr1:36097957 (GRCh38)
Gene constraint: LOEUF 1.139 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.03
Residue 575: the c1q domain; a UniProt-annotated variant site (in fecd1; uncertain significance); the 'nonhelical region (nc1)' 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-pro575leu (accessed [today's date]).

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