Is COL4A4 p.Pro334His (c.1001C>A) pathogenic?

COL4A4 p.Pro334His (c.1001C>A) is classified Uncertain significance in COL4A4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-03). AlphaMissense: likely benign (0.1021); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with COL4A4 p.Pro334His (c.1001C>A)?

COL4A4 p.Pro334His (c.1001C>A) is associated with Inborn genetic diseases (ClinVar).

How common is COL4A4 p.Pro334His (c.1001C>A) in the general population?

COL4A4 p.Pro334His (c.1001C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about COL4A4 p.Pro334His (c.1001C>A)?

AlphaMissense predicts likely benign (score 0.1021) — an in-silico prediction, not a clinical call.

COL4A4 p.Pro334His

c.1001C>A · VCV4840878

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1021 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1021	likely benign
REVEL	0.63	indeterminate
SaProt	LLR -10.07	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 140 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	22.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: COL4A4
Protein: p.Pro334His
Coding: c.1001C>A
MANE Select: NM_000092
Type: single nucleotide variant
Location: chr2:227101532 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 334: the 'triple-helical region' 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-pro334his (accessed [today's date]).

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