Is COL8A2 p.Leu335= (c.1005C>G) pathogenic?

COL8A2 p.Leu335= (c.1005C>G) is classified Benign in COL8A2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-28). Common (popmax 13.3%, eas) — too common for a highly-penetrant pathogenic allele.

COL8A2 p.Leu335=

Q: How common is COL8A2 p.Leu335= (c.1005C>G) in the general population?

COL8A2 p.Leu335= (c.1005C>G) is common (popmax 13.3%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1005C>G · rs79833067 · VCV1229188

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 13.3%, eas) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.12	GERP -4.2, phastCons 0.65
Overall
CADD	1.747	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 13.3% East Asian · 5,964/44,738 alleles

Filtering AF 13% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.9%

Overall 0.831% 13,382/1,609,848 alleles · common exomes 11,341/1,458,140 · genomes 2,041/151,708 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	13.3%	8
Admixed American	3.84%	26
Finnishnot grpmax-eligible	2.67%	37
Remaining individualsnot grpmax-eligible	1.58%	63
African / African-American	0.836%	120
South Asian	0.63%	159
Middle Eastern	0.596%	168
European (non-Finnish)	0.106%	941
Ashkenazi Jewishnot grpmax-eligible	0.0339%	2,949

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.Leu335=
Coding: c.1005C>G
MANE Select: NM_005202
dbSNP: rs79833067
Type: single nucleotide variant
Location: chr1:36098676 (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

Similar variants

COL8A2 p.Leu335Pro Uncertain significance ★ ⚠ same residue
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

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-leu335 (accessed [today's date]).

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