Is COL4A4 p.Pro655Ser (c.1963C>T) pathogenic?

COL4A4 p.Pro655Ser (c.1963C>T) is classified Uncertain significance in COL4A4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-13). AlphaMissense: likely benign (0.0903); Very rare (popmax 0.00373%, nfe); Associated with autosomal recessive Alport syndrome.

What condition is associated with COL4A4 p.Pro655Ser (c.1963C>T)?

COL4A4 p.Pro655Ser (c.1963C>T) is associated with autosomal recessive Alport syndrome, hematuria, benign familial, 1, Alport syndrome (ClinVar).

How common is COL4A4 p.Pro655Ser (c.1963C>T) in the general population?

COL4A4 p.Pro655Ser (c.1963C>T) is very rare (popmax 0.00373%, nfe) (gnomAD).

How is Alport syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about COL4A4 p.Pro655Ser (c.1963C>T)?

AlphaMissense predicts likely benign (score 0.0903) — an in-silico prediction, not a clinical call.

COL4A4 p.Pro655Ser

c.1963C>T · rs886055726 · VCV334727

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0903 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00373%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive Alport syndrome

Computational evidence

Protein change
AlphaMissense	0.0903	likely benign
REVEL	0.251	benign-leaning
SaProt	LLR -7.32	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 3.1	GERP -0.036, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 140 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	15.65	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 0.00373% European (non-Finnish) · 44/1,179,982 alleles

Filtering AF 0.00283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00291% 47/1,613,114 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00373%	26,818
Admixed American	0.00333%	29,992
Remaining individualsnot grpmax-eligible	0.0016%	62,396

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: COL4A4
Protein: p.Pro655Ser
Coding: c.1963C>T
MANE Select: NM_000092
dbSNP: rs886055726
Type: single nucleotide variant
Location: chr2:227077918 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 655: the 'triple-helical region' region; the 'disordered' region

Full COL4A4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive Alport syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hematuria, benign familial, 1 Alport syndrome

For Alport syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked dominant
Onset: Adolescent, Adult, Childhood, Elderly

Similar variants

COL4A4 c.1030-2A>C Likely pathogenic ★★ same condition
COL4A4 c.1099+1G>T Pathogenic/Likely pathogenic ★★ same condition
COL4A4 c.1369+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL4A4 c.1370-2A>C Likely pathogenic ★★ same condition
COL4A4 c.1459+1G>A Pathogenic ★★ same condition
COL4A4 c.1696+1G>A Likely pathogenic ★★ same condition
COL4A4 c.1696+1G>T Likely pathogenic ★★ same condition
COL4A4 c.1697-1G>A Pathogenic/Likely pathogenic ★★ 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/col4a4-p-pro655ser (accessed [today's date]).

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