Is COL4A4 p.Pro959= (c.2877C>T) pathogenic?

COL4A4 p.Pro959= (c.2877C>T) is classified Benign/Likely benign in COL4A4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-28). Low-frequency (popmax 1.19%, eas); Associated with autosomal recessive Alport syndrome.

What condition is associated with COL4A4 p.Pro959= (c.2877C>T)?

COL4A4 p.Pro959= (c.2877C>T) is associated with autosomal recessive Alport syndrome, Alport syndrome (ClinVar).

How common is COL4A4 p.Pro959= (c.2877C>T) in the general population?

COL4A4 p.Pro959= (c.2877C>T) is low-frequency (popmax 1.19%, eas) (gnomAD).

How is Alport syndrome inherited?

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

COL4A4 p.Pro959=

c.2877C>T · rs79470996 · VCV334712

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.19%, eas)

Conditions

autosomal recessive Alport syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.4	GERP -3.7
Overall
CADD	0.655	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.19% East Asian · 531/44,810 alleles

Filtering AF 1.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.07%

Overall 0.0385% 619/1,607,260 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	1.19%	84
Remaining individualsnot grpmax-eligible	0.0434%	2,306
Middle Eastern	0.0165%	6,048
South Asian	0.0121%	8,267
African / African-American	0.012%	8,309
Admixed American	0.00667%	14,999
European (non-Finnish)	0.00298%	33,542
Finnishnot grpmax-eligible	0.00156%	63,980

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.Pro959=
Coding: c.2877C>T
MANE Select: NM_000092
dbSNP: rs79470996
Type: single nucleotide variant
Location: chr2:227052396 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 959: 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: 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-pro959 (accessed [today's date]).

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