Is WDR72 p.Ser75Pro (c.223T>C) pathogenic?

WDR72 p.Ser75Pro (c.223T>C) is classified Uncertain significance in WDR72 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-07). AlphaMissense: likely benign (0.1383); Ultra-rare (popmax 0.029%, eas); Associated with amelogenesis imperfecta hypomaturation type 2A3.

What condition is associated with WDR72 p.Ser75Pro (c.223T>C)?

WDR72 p.Ser75Pro (c.223T>C) is associated with amelogenesis imperfecta hypomaturation type 2A3 (ClinVar).

How common is WDR72 p.Ser75Pro (c.223T>C) in the general population?

WDR72 p.Ser75Pro (c.223T>C) is ultra-rare (popmax 0.029%, eas) (gnomAD).

What do computational predictors say about WDR72 p.Ser75Pro (c.223T>C)?

AlphaMissense predicts likely benign (score 0.1383) — an in-silico prediction, not a clinical call.

WDR72 p.Ser75Pro

c.223T>C · rs193141655 · VCV2484608

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1383 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.029%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amelogenesis imperfecta hypomaturation type 2A3

Computational evidence

Protein change
AlphaMissense	0.1383	likely benign
REVEL	0.204	benign-leaning
SaProt	LLR -7.36	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 8.8	GERP 2.6, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 215 kb · p 0.0025 · regional, not allelic
Overall
CADD	26.3	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 0.029% East Asian · 13/44,860 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00093% 15/1,612,978 alleles · ultra-rare exomes 13/1,461,660 · genomes 2/151,318 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.029%	3,451
Admixed American	0.00167%	59,992
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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: WDR72
Protein: p.Ser75Pro
Coding: c.223T>C
MANE Select: NM_182758
dbSNP: rs193141655
Type: single nucleotide variant
Location: chr15:53722839 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.22

Full WDR72 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

amelogenesis imperfecta hypomaturation type 2A3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

WDR72 p.Arg30Ter Pathogenic/Likely pathogenic ★★ same condition
WDR72 p.Arg896Ter Pathogenic/Likely pathogenic ★★ same condition
WDR72 p.Lys333Ter Pathogenic ★★ same condition
WDR72 p.Trp978Ter Pathogenic ★★ same condition
WDR72 c.*3852T>G Uncertain significance ★★ same condition
WDR72 p.Ala1094Thr Uncertain significance ★★ ⚠ same condition
WDR72 p.Ala373Val Uncertain significance ★★ ⚠ same condition
WDR72 p.Ala402Val 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/wdr72-p-ser75pro (accessed [today's date]).

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