Is COL4A3 p.Pro663Ser (c.1987C>T) pathogenic?

COL4A3 p.Pro663Ser (c.1987C>T) is classified Uncertain significance in COL4A3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-09-15). AlphaMissense: likely benign (0.0773); Very rare (popmax 8.48e-05%, nfe); Associated with autosomal recessive Alport syndrome.

What condition is associated with COL4A3 p.Pro663Ser (c.1987C>T)?

COL4A3 p.Pro663Ser (c.1987C>T) is associated with autosomal recessive Alport syndrome, autosomal dominant Alport syndrome, hematuria, benign familial (ClinVar).

How common is COL4A3 p.Pro663Ser (c.1987C>T) in the general population?

COL4A3 p.Pro663Ser (c.1987C>T) is very rare (popmax 8.48e-05%, 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 COL4A3 p.Pro663Ser (c.1987C>T)?

AlphaMissense predicts likely benign (score 0.0773) — an in-silico prediction, not a clinical call.

COL4A3 p.Pro663Ser

c.1987C>T · rs747891356 · VCV1048647

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0773 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

autosomal recessive Alport syndrome

Computational evidence

Protein change
AlphaMissense	0.0773	likely benign
REVEL	0.387	indeterminate
SaProt	LLR -8.32	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.081	GERP -1.1
Regional constraint	o/e 0.84	unconstrained · MANE · 58 kb · p 2.1e-11 · regional, not allelic
Overall
CADD	7.906	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 8.48e-05% European (non-Finnish) · 1/1,179,774 alleles

Overall 6.2e-05% 1/1,613,894 alleles · very rare exomes 1/1,461,562 · genomes 0/152,332 · joint denominator

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.Pro663Ser
Coding: c.1987C>T
MANE Select: NM_000091
dbSNP: rs747891356
Type: single nucleotide variant
Location: chr2:227276444 (GRCh38)
Gene constraint: LOEUF 0.709 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 48.64 · 2 PDB
Residue 663: the 'triple-helical region' region; the 'disordered' region

Full COL4A3 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: autosomal dominant Alport syndrome hematuria, benign familial

For Alport syndrome (Orphanet):

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

Similar variants

COL4A3 p.Pro663Ala Uncertain significance ★ ⚠ same residue
COL4A3 p.Pro663Leu Uncertain significance ★ ⚠ same residue
COL4A3 p.Pro663= Likely benign ★ same residue
COL4A3 c.1114+1G>A Likely pathogenic ★★ same condition
COL4A3 c.1114+2T>C Pathogenic/Likely pathogenic ★★ same condition
COL4A3 c.1408+1G>C Pathogenic/Likely pathogenic ★★ same condition
COL4A3 c.1504+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL4A3 c.2489-1G>A 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/col4a3-p-pro663ser (accessed [today's date]).

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