Is COL8A2 p.Leu335Pro (c.1004T>C) pathogenic?

COL8A2 p.Leu335Pro (c.1004T>C) is classified Uncertain significance in COL8A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-30). AlphaMissense: likely benign (0.1016); Very rare (popmax 0.0022%, sas); Associated with Inborn genetic diseases.

What condition is associated with COL8A2 p.Leu335Pro (c.1004T>C)?

COL8A2 p.Leu335Pro (c.1004T>C) is associated with Inborn genetic diseases (ClinVar).

How common is COL8A2 p.Leu335Pro (c.1004T>C) in the general population?

COL8A2 p.Leu335Pro (c.1004T>C) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about COL8A2 p.Leu335Pro (c.1004T>C)?

AlphaMissense predicts likely benign (score 0.1016) — an in-silico prediction, not a clinical call.

COL8A2 p.Leu335Pro

c.1004T>C · rs1643618678 · VCV2607152

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1016 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1016	likely benign
REVEL	0.425	indeterminate
SaProt	LLR -5.11	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 6.4	GERP -0.54, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 1,954 bp · p 0.078 · regional, not allelic
Overall
CADD	18.53	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 0.0022% South Asian · 2/90,984 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000311% 5/1,609,502 alleles · very rare exomes 4/1,458,214 · genomes 1/151,288 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,492
European (non-Finnish)	0.000254%	393,032

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.Leu335Pro
Coding: c.1004T>C
MANE Select: NM_005202
dbSNP: rs1643618678
Type: single nucleotide variant
Location: chr1:36098677 (GRCh38)
Gene constraint: LOEUF 1.139 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.03
Residue 335: 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.Leu335= Benign ★★ 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-leu335pro (accessed [today's date]).

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