Is COL4A2 p.Pro739Ser (c.2215C>T) pathogenic?

COL4A2 p.Pro739Ser (c.2215C>T) is classified Uncertain significance in COL4A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). AlphaMissense: likely benign (0.2124); Very rare (popmax 0.00385%, amr); Associated with Inborn genetic diseases.

What condition is associated with COL4A2 p.Pro739Ser (c.2215C>T)?

COL4A2 p.Pro739Ser (c.2215C>T) is associated with Inborn genetic diseases (ClinVar).

How common is COL4A2 p.Pro739Ser (c.2215C>T) in the general population?

COL4A2 p.Pro739Ser (c.2215C>T) is very rare (popmax 0.00385%, amr) (gnomAD).

What do computational predictors say about COL4A2 p.Pro739Ser (c.2215C>T)?

AlphaMissense predicts likely benign (score 0.2124) — an in-silico prediction, not a clinical call.

COL4A2 p.Pro739Ser

c.2215C>T · VCV4616245

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2124 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00385%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2124	likely benign
REVEL	0.525	indeterminate
SaProt	LLR -7.47	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 3.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 62 kb · p 6e-16 · regional, not allelic
Overall
CADD	21.5	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 0.00385% Admixed American · 2/51,892 alleles

Filtering AF 0.000639% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000239%

Overall 0.000386% 6/1,556,060 alleles · very rare exomes 6/1,403,740 · genomes 0/152,320 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00385%	25,946
European (non-Finnish)	0.000348%	287,405

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: COL4A2
Protein: p.Pro739Ser
Coding: c.2215C>T
MANE Select: NM_001846
Type: single nucleotide variant
Location: chr13:110472940 (GRCh38)
Gene constraint: LOEUF 0.618 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 47.97 · 4 PDB
Residue 739: the 'triple-helical region' region; the 'disordered' region

Full COL4A2 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

COL4A2 p.Pro739His Uncertain significance ★ ⚠ same residue
COL4A2 p.Arg1193Cys Uncertain significance ★★ ⚠ same condition
COL4A2 p.Arg1336Lys Uncertain significance ★★ ⚠ same condition
COL4A2 p.Arg1452Trp Uncertain significance ★★ ⚠ same condition
COL4A2 p.Arg1540Trp Uncertain significance ★★ ⚠ same condition
COL4A2 p.Arg1560Gln Uncertain significance ★★ ⚠ same condition
COL4A2 p.Arg1589His Uncertain significance ★★ ⚠ same condition
COL4A2 p.Arg1617Gln 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/col4a2-p-pro739ser (accessed [today's date]).

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