Is SRD5A2 p.Pro9Ser (c.25C>T) pathogenic?

SRD5A2 p.Pro9Ser (c.25C>T) is classified Uncertain significance in SRD5A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-05). AlphaMissense: likely benign (0.0988); Very rare (popmax 6.21e-05%); Associated with 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency.

What condition is associated with SRD5A2 p.Pro9Ser (c.25C>T)?

SRD5A2 p.Pro9Ser (c.25C>T) is associated with 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency (ClinVar).

How common is SRD5A2 p.Pro9Ser (c.25C>T) in the general population?

SRD5A2 p.Pro9Ser (c.25C>T) is very rare (popmax 6.21e-05%) (gnomAD).

What do computational predictors say about SRD5A2 p.Pro9Ser (c.25C>T)?

AlphaMissense predicts likely benign (score 0.0988) — an in-silico prediction, not a clinical call.

SRD5A2 p.Pro9Ser

Q: How is 46,XY difference of sex development due to 5-alpha-reductase 2 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.25C>T · rs868322910 · VCV1487365

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0988 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.21e-05%)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Conditions

46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency

Computational evidence

Protein change
AlphaMissense	0.0988	likely benign
SaProt	LLR -8.11	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -0.31, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 55 kb · p 0.17 · regional, not allelic
Overall
CADD	16.78	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; SaProt is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.21e-05%

Overall 6.21e-05% 1/1,609,054 alleles · very rare exomes 1/1,456,716 · genomes 0/152,338 · joint denominator

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: SRD5A2
Protein: p.Pro9Ser
Coding: c.25C>T
MANE Select: NM_000348
dbSNP: rs868322910
Type: single nucleotide variant
Location: chr2:31580876 (GRCh38)
Gene constraint: LOEUF 1.717 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 94.56 · 1 PDB
Residue 9: an α-helix

Full SRD5A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For 46,XY difference of sex development due to 5-alpha-reductase 2 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood, Infancy, Neonatal

Similar variants

SRD5A2 p.Pro9= Likely benign ★ same residue
SRD5A2 c.282-2A>G Pathogenic ★★ same condition
SRD5A2 c.698+1G>T Pathogenic/Likely pathogenic ★★ same condition
SRD5A2 p.Ala207Asp Pathogenic/Likely pathogenic ★★ same condition
SRD5A2 p.Ala228Thr Pathogenic/Likely pathogenic ★★ same condition
SRD5A2 p.Ala65Pro Pathogenic/Likely pathogenic ★★ same condition
SRD5A2 p.Arg103Ter Pathogenic ★★ same condition
SRD5A2 p.Arg145Trp Pathogenic/Likely pathogenic ★★ ⚠ 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/srd5a2-p-pro9ser (accessed [today's date]).

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