Is COL4A1 p.Pro137Ser (c.409C>T) pathogenic?

COL4A1 p.Pro137Ser (c.409C>T) is classified Uncertain significance in COL4A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-16). AlphaMissense: likely benign (0.0895); Very rare (popmax 0.00788%, nfe); Associated with autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome.

How common is COL4A1 p.Pro137Ser (c.409C>T) in the general population?

COL4A1 p.Pro137Ser (c.409C>T) is very rare (popmax 0.00788%, nfe) (gnomAD).

How is HANAC syndrome inherited?

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

What do computational predictors say about COL4A1 p.Pro137Ser (c.409C>T)?

AlphaMissense predicts likely benign (score 0.0895) — an in-silico prediction, not a clinical call.

COL4A1 p.Pro137Ser

Q: What condition is associated with COL4A1 p.Pro137Ser (c.409C>T)?

COL4A1 p.Pro137Ser (c.409C>T) is associated with autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome, brain small vessel disease 1 with or without ocular anomalies (ClinVar).

c.409C>T · rs148290885 · VCV883375

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0895 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00788%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

Computational evidence

Protein change
AlphaMissense	0.0895	likely benign
REVEL	0.287	benign-leaning
SaProt	LLR -8.50	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 9.8	GERP 1.3, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 33 kb · p 2.1e-05 · regional, not allelic
Overall
CADD	19.26	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 0.00788% European (non-Finnish) · 93/1,180,016 alleles

Filtering AF 0.00656% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00608%

Overall 0.00576% 93/1,613,954 alleles · very rare

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: COL4A1
Protein: p.Pro137Ser
Coding: c.409C>T
MANE Select: NM_001845
dbSNP: rs148290885
Type: single nucleotide variant
Location: chr13:110211901 (GRCh38)
Gene constraint: LOEUF 0.238 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.43 · 4 PDB
Residue 137: the 'disordered' region

Full COL4A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: brain small vessel disease 1 with or without ocular anomalies

For HANAC syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

COL4A1 c.1991-2A>G Likely pathogenic ★★ same condition
COL4A1 c.2458+1G>A Pathogenic ★★ same condition
COL4A1 c.2458+2T>C Pathogenic/Likely pathogenic ★★ same condition
COL4A1 c.3742+1G>A Pathogenic ★★ same condition
COL4A1 c.388-1G>C Pathogenic/Likely pathogenic ★★ same condition
COL4A1 c.4250-1G>A Pathogenic/Likely pathogenic ★★ same condition
COL4A1 c.*32G>A Pathogenic/Likely pathogenic ★★ same condition
COL4A1 p.Arg1063Ter 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/col4a1-p-pro137ser (accessed [today's date]).

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