Is AR p.Leu548Phe (c.1644G>T) pathogenic?

AR p.Leu548Phe (c.1644G>T) is classified Benign in AR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-05). AlphaMissense: likely benign (0.2878); Ultra-rare (popmax 0.0914%, mid); Associated with prostate cancer, hereditary, X-linked 3.

What condition is associated with AR p.Leu548Phe (c.1644G>T)?

AR p.Leu548Phe (c.1644G>T) is associated with prostate cancer, hereditary, X-linked 3, Kennedy disease, androgen insensitivity syndrome (ClinVar).

How common is AR p.Leu548Phe (c.1644G>T) in the general population?

AR p.Leu548Phe (c.1644G>T) is ultra-rare (popmax 0.0914%, mid) (gnomAD).

What do computational predictors say about AR p.Leu548Phe (c.1644G>T)?

AlphaMissense predicts likely benign (score 0.2878) — an in-silico prediction, not a clinical call.

AR p.Leu548Phe

c.1644G>T · rs139524801 · VCV1685538

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2878 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0914%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

prostate cancer, hereditary, X-linked 3

Computational evidence

Protein change
AlphaMissense	0.2878	likely benign
REVEL	0.5	indeterminate
SaProt	LLR -6.52	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.73	GERP -2.5, phastCons 1
Overall
CADD	13.8	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 0.0914% Middle Eastern · 4/4,374 alleles

Filtering AF 0.0312% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0188%

Overall 0.0154% 186/1,209,671 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0914%	1,093
South Asian	0.0229%	4,373
European (non-Finnish)	0.0175%	5,701
Remaining individualsnot grpmax-eligible	0.0126%	7,929
Admixed American	0.00657%	15,211
African / African-American	0.0035%	28,579
Finnishnot grpmax-eligible	0.00215%	46,603

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.Leu548Phe
Coding: c.1644G>T
MANE Select: NM_000044
dbSNP: rs139524801
Type: single nucleotide variant
Location: chrX:67643283 (GRCh38)
Structure: AlphaFold pLDDT 58.85 · 95 PDB
Residue 548: the 'interaction with znf318' region; the 'modulating' region; a UniProt-annotated variant site (in pais)

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

Disease context

prostate cancer, hereditary, X-linked 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Kennedy disease androgen insensitivity syndrome

Similar variants

AR p.Leu548= Likely benign ★ same residue
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

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-leu548phe (accessed [today's date]).

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