Is COL4A4 p.Pro883Thr (c.2647C>A) pathogenic?

COL4A4 p.Pro883Thr (c.2647C>A) is classified Conflicting classifications of pathogenicity in COL4A4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-06). AlphaMissense: likely benign (0.0721); Ultra-rare (popmax 0.096%, afr); Associated with Inborn genetic diseases.

What condition is associated with COL4A4 p.Pro883Thr (c.2647C>A)?

COL4A4 p.Pro883Thr (c.2647C>A) is associated with Inborn genetic diseases (ClinVar).

How common is COL4A4 p.Pro883Thr (c.2647C>A) in the general population?

COL4A4 p.Pro883Thr (c.2647C>A) is ultra-rare (popmax 0.096%, afr) (gnomAD).

What do computational predictors say about COL4A4 p.Pro883Thr (c.2647C>A)?

AlphaMissense predicts likely benign (score 0.0721) — an in-silico prediction, not a clinical call.

COL4A4 p.Pro883Thr

c.2647C>A · rs200761108 · VCV930121

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0721 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.096%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0721	likely benign
REVEL	0.277	benign-leaning
SaProt	LLR -7.86	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 2	GERP 0.21, phastCons 0.015
Regional constraint	o/e 0.91	unconstrained · MANE · 140 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	7.399	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 0.096% African / African-American · 72/75,012 alleles

Filtering AF 0.0781% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0716%

Overall 0.00477% 77/1,613,320 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.096%	1,042
Remaining individualsnot grpmax-eligible	0.0048%	20,825
Admixed American	0.00167%	60,022
European (non-Finnish)	8.48e-05%	1,179,344

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.Pro883Thr
Coding: c.2647C>A
MANE Select: NM_000092
dbSNP: rs200761108
Type: single nucleotide variant
Location: chr2:227056014 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 883: 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.Pro883Ala Uncertain significance ★ ⚠ same residue
COL4A4 p.Pro883Leu Uncertain significance ★ same residue
COL4A4 p.Pro883Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
COL4A4 p.Pro883= Likely benign ★ same residue
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

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-pro883thr (accessed [today's date]).

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