Is COL4A6 p.Pro99Ser (c.295C>T) pathogenic?

COL4A6 p.Pro99Ser (c.295C>T) is classified Uncertain significance in COL4A6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-28). AlphaMissense: likely benign (0.1442); Very rare (popmax 0.00729%, nfe).

How common is COL4A6 p.Pro99Ser (c.295C>T) in the general population?

COL4A6 p.Pro99Ser (c.295C>T) is very rare (popmax 0.00729%, nfe) (gnomAD).

What do computational predictors say about COL4A6 p.Pro99Ser (c.295C>T)?

AlphaMissense predicts likely benign (score 0.1442) — an in-silico prediction, not a clinical call.

COL4A6 p.Pro99Ser

c.295C>T · rs754228628 · VCV2712080

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1442 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00729%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1442	likely benign
REVEL	0.704	pathogenic-leaning
SaProt	LLR -7.96	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 281 kb · p 0.15 · regional, not allelic
Overall
CADD	22.0	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 P100S vs ClinVar P99S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00729% European (non-Finnish) · 65/892,179 alleles

Filtering AF 0.00586% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00534%

Overall 0.00555% 67/1,206,132 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00729%	13,726
Remaining individualsnot grpmax-eligible	0.00211%	47,492
African / African-American	0.00176%	56,893

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.Pro99Ser
Coding: c.295C>T
MANE Select: NM_033641
dbSNP: rs754228628
Type: single nucleotide variant
Location: chrX:108219727 (GRCh38)
Structure: AlphaFold pLDDT 48.27
Residue 99: the 'triple-helical region' 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-pro99ser (accessed [today's date]).

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