Is COL4A6 p.Pro208Arg (c.623C>G) pathogenic?

COL4A6 p.Pro208Arg (c.623C>G) is classified Conflicting classifications of pathogenicity in COL4A6 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-06-22). AlphaMissense: likely benign (0.0815); Rare (popmax 0.407%, eas).

How common is COL4A6 p.Pro208Arg (c.623C>G) in the general population?

COL4A6 p.Pro208Arg (c.623C>G) is rare (popmax 0.407%, eas) (gnomAD).

What do computational predictors say about COL4A6 p.Pro208Arg (c.623C>G)?

AlphaMissense predicts likely benign (score 0.0815) — an in-silico prediction, not a clinical call.

COL4A6 p.Pro208Arg

c.623C>G · rs2295919 · VCV1318245

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0815 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.407%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0815	likely benign
REVEL	0.417	indeterminate
SaProt	LLR -9.81	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -2.5, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 281 kb · p 0.15 · regional, not allelic
Overall
CADD	16.11	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P209R vs ClinVar P208R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.407% East Asian · 137/33,646 alleles

Filtering AF 0.352% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.331%

Overall 0.0115% 139/1,204,825 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.407%	246
Remaining individualsnot grpmax-eligible	0.00422%	23,694

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: COL4A6
Protein: p.Pro208Arg
Coding: c.623C>G
MANE Select: NM_033641
dbSNP: rs2295919
Type: single nucleotide variant
Location: chrX:108205682 (GRCh38)
Structure: AlphaFold pLDDT 48.27
Residue 208: the 'triple-helical region' region; the 'disordered' region

Full COL4A6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COL4A6 c.3970+5G>A Uncertain significance ★★ same type
COL4A6 p.Ala1275Thr Uncertain significance ★★ ⚠ same type
COL4A6 p.Ala398Ser Uncertain significance ★★ ⚠ same type
COL4A6 p.Ala421Gly Uncertain significance ★★ ⚠ same type
COL4A6 p.Ala748Val Uncertain significance ★★ ⚠ same type
COL4A6 p.Ala886Thr Uncertain significance ★★ ⚠ same type
COL4A6 p.Arg1025Trp Uncertain significance ★★ ⚠ same type
COL4A6 p.Arg1262Gln 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/col4a6-p-pro208arg (accessed [today's date]).

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