Is ZFPM2 p.Pro41Ala (c.121C>G) pathogenic?

ZFPM2 p.Pro41Ala (c.121C>G) is classified Conflicting classifications of pathogenicity in ZFPM2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2024-10-31). AlphaMissense: likely benign (0.0701); Ultra-rare (popmax 0.0356%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ZFPM2 p.Pro41Ala (c.121C>G)?

ZFPM2 p.Pro41Ala (c.121C>G) is associated with Inborn genetic diseases, 46,XY sex reversal 9 (ClinVar).

How common is ZFPM2 p.Pro41Ala (c.121C>G) in the general population?

ZFPM2 p.Pro41Ala (c.121C>G) is ultra-rare (popmax 0.0356%, nfe) (gnomAD).

What do computational predictors say about ZFPM2 p.Pro41Ala (c.121C>G)?

AlphaMissense predicts likely benign (score 0.0701) — an in-silico prediction, not a clinical call.

ZFPM2 p.Pro41Ala

c.121C>G · rs199535268 · VCV1061068

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0701 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0356%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0701	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -6.47	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 3.3	GERP 0.62, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 485 kb · p 0.035 · regional, not allelic
Overall
CADD	17.72	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 0.0356% European (non-Finnish) · 420/1,179,696 alleles

Filtering AF 0.0327% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0317%

Overall 0.0268% 432/1,613,512 alleles · ultra-rare exomes 411/1,461,376 · genomes 21/152,136 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0356%	2,809
Remaining individualsnot grpmax-eligible	0.016%	6,245
African / African-American	0.00267%	37,449

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.Pro41Ala
Coding: c.121C>G
MANE Select: NM_012082
dbSNP: rs199535268
Type: single nucleotide variant
Location: chr8:105419224 (GRCh38)
Gene constraint: LOEUF 0.274 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 51.93
Residue 41: the 'disordered' region

Full ZFPM2 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

Also linked: 46,XY sex reversal 9

Similar variants

ZFPM2 p.Arg117Gln Uncertain significance ★★ ⚠ same condition
ZFPM2 p.Arg222His 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

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-pro41ala (accessed [today's date]).

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