Is ZFPM2 p.Pro493Ser (c.1477C>T) pathogenic?

ZFPM2 p.Pro493Ser (c.1477C>T) is classified Uncertain significance in ZFPM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-28). AlphaMissense: likely benign (0.0791); Very rare (popmax 0.00153%, nfe); Associated with 46,XY sex reversal 9.

What condition is associated with ZFPM2 p.Pro493Ser (c.1477C>T)?

ZFPM2 p.Pro493Ser (c.1477C>T) is associated with 46,XY sex reversal 9 (ClinVar).

How common is ZFPM2 p.Pro493Ser (c.1477C>T) in the general population?

ZFPM2 p.Pro493Ser (c.1477C>T) is very rare (popmax 0.00153%, nfe) (gnomAD).

What do computational predictors say about ZFPM2 p.Pro493Ser (c.1477C>T)?

AlphaMissense predicts likely benign (score 0.0791) — an in-silico prediction, not a clinical call.

ZFPM2 p.Pro493Ser

c.1477C>T · VCV3670391

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0791 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

46,XY sex reversal 9

Computational evidence

Protein change
AlphaMissense	0.0791	likely benign
REVEL	0.237	benign-leaning
SaProt	LLR -6.61	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 1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 485 kb · p 0.035 · regional, not allelic
Overall
CADD	23.3	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 0.00153% European (non-Finnish) · 18/1,179,872 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00149% 24/1,613,784 alleles · very rare exomes 21/1,461,690 · genomes 3/152,094 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00961%	10,411
European (non-Finnish)grpmax	0.00153%	65,548

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ZFPM2
Protein: p.Pro493Ser
Coding: c.1477C>T
MANE Select: NM_012082
Type: single nucleotide variant
Location: chr8:105801559 (GRCh38)
Gene constraint: LOEUF 0.274 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 51.93

Full ZFPM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

46,XY sex reversal 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ZFPM2 p.Arg117Gln Uncertain significance ★★ ⚠ same condition
ZFPM2 p.Asn136Ser Uncertain significance ★★ ⚠ same condition
ZFPM2 p.Asp96Tyr Uncertain significance ★★ ⚠ same condition
ZFPM2 p.Gln707Glu Uncertain significance ★★ ⚠ same condition
ZFPM2 p.Gly164Arg Uncertain significance ★★ ⚠ same condition
ZFPM2 p.Gly531Asp Uncertain significance ★★ ⚠ same condition
ZFPM2 p.Gly547Arg Uncertain significance ★★ ⚠ same condition
ZFPM2 p.His699Pro 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/zfpm2-p-pro493ser (accessed [today's date]).

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