Is COL4A3 p.Pro655Ser (c.1963C>T) pathogenic?

COL4A3 p.Pro655Ser (c.1963C>T) is classified Uncertain significance in COL4A3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-27). AlphaMissense: likely benign (0.0857); Very rare (popmax 0.00267%, afr); Associated with autosomal dominant Alport syndrome.

What condition is associated with COL4A3 p.Pro655Ser (c.1963C>T)?

COL4A3 p.Pro655Ser (c.1963C>T) is associated with autosomal dominant Alport syndrome, Alport syndrome 3b, autosomal recessive, hematuria, benign familial, 2 (ClinVar).

How common is COL4A3 p.Pro655Ser (c.1963C>T) in the general population?

COL4A3 p.Pro655Ser (c.1963C>T) is very rare (popmax 0.00267%, afr) (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 COL4A3 p.Pro655Ser (c.1963C>T)?

AlphaMissense predicts likely benign (score 0.0857) — an in-silico prediction, not a clinical call.

COL4A3 p.Pro655Ser

c.1963C>T · VCV3586036

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0857 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal dominant Alport syndrome

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.0857	likely benign
REVEL	0.564	indeterminate
SaProt	LLR -8.88	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Pangolin	Δ0.20	loss · gain 0.03 · independent
Constraint at this position
Conservation	phyloP 2.7	GERP 1.8, phastCons 0.84
Regional constraint	o/e 0.84	unconstrained · MANE · 58 kb · p 2.1e-11 · regional, not allelic
Overall
CADD	22.2	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 0.00267% African / African-American · 2/74,928 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000805% 13/1,614,058 alleles · very rare exomes 11/1,461,848 · genomes 2/152,210 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,464
European (non-Finnish)	0.000932%	107,274

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: COL4A3
Protein: p.Pro655Ser
Coding: c.1963C>T
MANE Select: NM_000091
Type: single nucleotide variant
Location: chr2:227276420 (GRCh38)

Full COL4A3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: Alport syndrome 3b, autosomal recessive hematuria, benign familial, 2

For Alport syndrome (Orphanet):

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

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/col4a3-p-pro655ser (accessed [today's date]).

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