Is COL4A4 p.Pro531Ser (c.1591C>T) pathogenic?

COL4A4 p.Pro531Ser (c.1591C>T) is classified Conflicting classifications of pathogenicity in COL4A4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-13). AlphaMissense: likely benign (0.074); Very rare (popmax 0.0022%, nfe); Associated with Inborn genetic diseases.

What condition is associated with COL4A4 p.Pro531Ser (c.1591C>T)?

COL4A4 p.Pro531Ser (c.1591C>T) is associated with Inborn genetic diseases (ClinVar).

How common is COL4A4 p.Pro531Ser (c.1591C>T) in the general population?

COL4A4 p.Pro531Ser (c.1591C>T) is very rare (popmax 0.0022%, nfe) (gnomAD).

What do computational predictors say about COL4A4 p.Pro531Ser (c.1591C>T)?

AlphaMissense predicts likely benign (score 0.074) — an in-silico prediction, not a clinical call.

COL4A4 p.Pro531Ser

c.1591C>T · rs745843581 · VCV2156455

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.074 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.074	likely benign
REVEL	0.238	benign-leaning
SaProt	LLR -7.12	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 4.9	GERP -0.055, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 140 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	16.37	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 0.0022% European (non-Finnish) · 26/1,180,012 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.0018% 29/1,613,978 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0022%	45,385
Remaining individualsnot grpmax-eligible	0.0016%	62,486
Finnishnot grpmax-eligible	0.00156%	64,004
African / African-American	0.00134%	74,900

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.Pro531Ser
Coding: c.1591C>T
MANE Select: NM_000092
dbSNP: rs745843581
Type: single nucleotide variant
Location: chr2:227088685 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 531: the 'triple-helical region' region; the 'disordered' region

Full COL4A4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COL4A4 p.Arg349Ter Pathogenic/Likely pathogenic ★★ same condition
COL4A4 p.Cys1588Ser Likely pathogenic ★★ same condition
COL4A4 c.4522+6G>A Uncertain significance ★★ same condition
COL4A4 p.Ala1546Thr Uncertain significance ★★ ⚠ same condition
COL4A4 p.Arg1565Cys Uncertain significance ★★ ⚠ same condition
COL4A4 p.Arg641Gln Uncertain significance ★★ ⚠ same condition
COL4A4 p.Arg811Thr Uncertain significance ★★ ⚠ same condition
COL4A4 p.Arg97His Uncertain significance ★★ ⚠ 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-pro531ser (accessed [today's date]).

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