Is SRD5A2 p.Phe234Leu (c.702C>G) pathogenic?

SRD5A2 p.Phe234Leu (c.702C>G) is classified Conflicting classifications of pathogenicity in SRD5A2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-26). AlphaMissense: likely pathogenic (0.9555); Rare (popmax 0.419%, eas); Associated with 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency.

What condition is associated with SRD5A2 p.Phe234Leu (c.702C>G)?

SRD5A2 p.Phe234Leu (c.702C>G) is associated with 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency (ClinVar).

How common is SRD5A2 p.Phe234Leu (c.702C>G) in the general population?

SRD5A2 p.Phe234Leu (c.702C>G) is rare (popmax 0.419%, eas) (gnomAD).

What do computational predictors say about SRD5A2 p.Phe234Leu (c.702C>G)?

AlphaMissense predicts likely pathogenic (score 0.9555) — an in-silico prediction, not a clinical call.

SRD5A2 p.Phe234Leu

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.702C>G · rs9332966 · VCV97414

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9555 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.419%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.9555	likely pathogenic · top 4% in SRD5A2
SaProt	LLR -6.29	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP -0.049, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 55 kb · p 0.17 · regional, not allelic
Overall
CADD	23.4	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

Grpmax group 0.419% East Asian · 183/43,716 alleles

Filtering AF 0.369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.35%

Overall 0.0123% 193/1,571,460 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.419%	239
Remaining individualsnot grpmax-eligible	0.0131%	7,623
Admixed American	0.00179%	55,760
European (non-Finnish)	8.67e-05%	1,153,280

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.Phe234Leu
Coding: c.702C>G
MANE Select: NM_000348
dbSNP: rs9332966
Type: single nucleotide variant
Location: chr2:31526259 (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 234: a UniProt-annotated variant site (increased affinity for testosterone; increased affinity for nadph; decreased vmax and); 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 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
SRD5A2 p.Arg227Gln 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-phe234leu (accessed [today's date]).

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