Is COL4A4 p.Pro416Ala (c.1246C>G) pathogenic?

COL4A4 p.Pro416Ala (c.1246C>G) is classified Conflicting classifications of pathogenicity in COL4A4 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-02-12). AlphaMissense: likely benign (0.0717); Ultra-rare (popmax 0.06%, afr); Associated with autosomal recessive Alport syndrome.

What condition is associated with COL4A4 p.Pro416Ala (c.1246C>G)?

COL4A4 p.Pro416Ala (c.1246C>G) is associated with autosomal recessive Alport syndrome, glomerulonephritis, hematuria, benign familial, 1 (ClinVar).

How common is COL4A4 p.Pro416Ala (c.1246C>G) in the general population?

COL4A4 p.Pro416Ala (c.1246C>G) is ultra-rare (popmax 0.06%, 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 COL4A4 p.Pro416Ala (c.1246C>G)?

AlphaMissense predicts likely benign (score 0.0717) — an in-silico prediction, not a clinical call.

COL4A4 p.Pro416Ala

c.1246C>G · rs372841765 · VCV930187

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0717 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.06%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal recessive Alport syndrome

Computational evidence

Protein change
AlphaMissense	0.0717	likely benign
REVEL	0.356	indeterminate
SaProt	LLR -5.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 140 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.06% African / African-American · 45/75,032 alleles

Filtering AF 0.046% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0411%

Overall 0.0031% 50/1,613,880 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.06%	1,667
Middle Eastern	0.0167%	5,992
Remaining individualsnot grpmax-eligible	0.0032%	31,244
Admixed American	0.00167%	60,012
South Asian	0.0011%	91,076

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.Pro416Ala
Coding: c.1246C>G
MANE Select: NM_000092
dbSNP: rs372841765
Type: single nucleotide variant
Location: chr2:227094248 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 416: 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: glomerulonephritis hematuria, benign familial, 1

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.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
COL4A4 c.1803+2T>C 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-pro416ala (accessed [today's date]).

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