Is SRD5A2 p.Ala65Pro (c.193G>C) pathogenic?

SRD5A2 p.Ala65Pro (c.193G>C) is classified Pathogenic/Likely pathogenic in SRD5A2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-02-09). AlphaMissense: ambiguous (0.5134); Absent from gnomAD v4.1; Associated with 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency.

What condition is associated with SRD5A2 p.Ala65Pro (c.193G>C)?

SRD5A2 p.Ala65Pro (c.193G>C) is associated with 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency (ClinVar).

How common is SRD5A2 p.Ala65Pro (c.193G>C) in the general population?

SRD5A2 p.Ala65Pro (c.193G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SRD5A2 p.Ala65Pro (c.193G>C)?

AlphaMissense predicts ambiguous (score 0.5134) — an in-silico prediction, not a clinical call.

SRD5A2 p.Ala65Pro

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.193G>C · rs1186430097 · VCV988403

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5134 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,604,540)

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.5134	ambiguous
SaProt	LLR -13.99	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.68	GERP 0.29
Regional constraint	o/e 1.08	unconstrained · MANE · 55 kb · p 0.17 · regional, not allelic
Overall
CADD	18.85	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; SaProt is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,604,540). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SRD5A2
Protein: p.Ala65Pro
Coding: c.193G>C
MANE Select: NM_000348
dbSNP: rs1186430097
Type: single nucleotide variant
Location: chr2:31580708 (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 65: an α-helix; a UniProt-annotated variant site (found in individual with micropenis)

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.Ala65Thr Pathogenic ★ ⚠ same residue
SRD5A2 p.Ala65= 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.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-ala65pro (accessed [today's date]).

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