Is COL4A6 p.Ser661Pro (c.1981T>C) pathogenic?

COL4A6 p.Ser661Pro (c.1981T>C) is classified Uncertain significance in COL4A6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-13). AlphaMissense: likely benign (0.0634); Ultra-rare (popmax 0.0229%, mid).

How common is COL4A6 p.Ser661Pro (c.1981T>C) in the general population?

COL4A6 p.Ser661Pro (c.1981T>C) is ultra-rare (popmax 0.0229%, mid) (gnomAD).

What do computational predictors say about COL4A6 p.Ser661Pro (c.1981T>C)?

AlphaMissense predicts likely benign (score 0.0634) — an in-silico prediction, not a clinical call.

COL4A6 p.Ser661Pro

c.1981T>C · rs772716977 · VCV1385706

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0634 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0229%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0634	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -4.68	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.14	GERP -2.2
Regional constraint	o/e 0.96	unconstrained · MANE · 281 kb · p 0.15 · regional, not allelic
Overall
CADD	0.022	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S662P vs ClinVar S661P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0229% Middle Eastern · 1/4,371 alleles

Filtering AF 0.00699% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00646%

Overall 0.00711% 86/1,209,251 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0229%	4,371
European (non-Finnish)	0.00861%	11,616
Remaining individualsnot grpmax-eligible	0.00841%	11,892
Admixed American	0.00436%	22,913
South Asian	0.00353%	28,343

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.Ser661Pro
Coding: c.1981T>C
MANE Select: NM_033641
dbSNP: rs772716977
Type: single nucleotide variant
Location: chrX:108180939 (GRCh38)
Structure: AlphaFold pLDDT 48.27
Residue 661: 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-ser661pro (accessed [today's date]).

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