Is AR p.Ser434Phe (c.1301C>T) pathogenic?

AR p.Ser434Phe (c.1301C>T) is classified Conflicting classifications of pathogenicity in AR (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-05). AlphaMissense: ambiguous (0.4175); Rare (popmax 0.159%, mid); Associated with prostate cancer.

What condition is associated with AR p.Ser434Phe (c.1301C>T)?

AR p.Ser434Phe (c.1301C>T) is associated with prostate cancer, male infertility, hypospadias 1, X-linked (ClinVar).

How common is AR p.Ser434Phe (c.1301C>T) in the general population?

AR p.Ser434Phe (c.1301C>T) is rare (popmax 0.159%, mid) (gnomAD).

What do computational predictors say about AR p.Ser434Phe (c.1301C>T)?

AlphaMissense predicts ambiguous (score 0.4175) — an in-silico prediction, not a clinical call.

AR p.Ser434Phe

c.1301C>T · rs748457992 · VCV1167626

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4175 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.159%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

prostate cancer

Computational evidence

Protein change
AlphaMissense	0.4175	ambiguous
REVEL	0.832	moderately pathogenic-leaning
SaProt	LLR -8.63	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.1, phastCons 1
Overall
CADD	23.0	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 0.159% Middle Eastern · 5/3,141 alleles

Filtering AF 0.0627% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0407%

Overall 0.0134% 159/1,182,301 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.159%	628
European (non-Finnish)	0.0163%	6,123
Remaining individualsnot grpmax-eligible	0.0151%	6,631
Admixed American	0.00464%	21,538
Finnishnot grpmax-eligible	0.00231%	43,311

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: AR
Protein: p.Ser434Phe
Coding: c.1301C>T
MANE Select: NM_000044
dbSNP: rs748457992
Type: single nucleotide variant
Location: chrX:67546447 (GRCh38)
Structure: AlphaFold pLDDT 58.85 · 95 PDB
Residue 434: the 'interaction with znf318' region; the 'modulating' region

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

Disease context

prostate cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: male infertility hypospadias 1, X-linked partial androgen insensitivity syndrome Kennedy disease androgen insensitivity syndrome

Similar variants

AR c.1768+2T>C Pathogenic/Likely pathogenic ★★ same condition
AR c.1769-11T>A Pathogenic ★★ same condition
AR c.2450-6C>G Pathogenic ★★ same condition
AR p.Ala588Pro Pathogenic/Likely pathogenic ★★ same condition
AR p.Ala597Thr Pathogenic ★★ same condition
AR p.Ala688Val Pathogenic/Likely pathogenic ★★ same condition
AR p.Ala766Thr Pathogenic ★★ same condition
AR p.Ala871Val 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/ar-p-ser434phe (accessed [today's date]).

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