Is AR p.Pro549Ser (c.1645C>T) pathogenic?

AR p.Pro549Ser (c.1645C>T) is classified Uncertain significance in AR (ClinVar, Single submitter, 2 submitters; last evaluated 2024-06-03). AlphaMissense: likely pathogenic (0.744); Very rare (popmax 0.000112%, nfe); Associated with hypospadias 1, X-linked.

What condition is associated with AR p.Pro549Ser (c.1645C>T)?

AR p.Pro549Ser (c.1645C>T) is associated with hypospadias 1, X-linked (ClinVar).

How common is AR p.Pro549Ser (c.1645C>T) in the general population?

AR p.Pro549Ser (c.1645C>T) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about AR p.Pro549Ser (c.1645C>T)?

AlphaMissense predicts likely pathogenic (score 0.744) — an in-silico prediction, not a clinical call.

AR p.Pro549Ser

c.1645C>T · rs137852588 · VCV9840

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.744 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypospadias 1, X-linked

Computational evidence

Protein change
AlphaMissense	0.744	likely pathogenic
REVEL	0.876	moderately pathogenic-leaning
SaProt	LLR -6.73	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.6, phastCons 1
Overall
CADD	23.7	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 0.000112% European (non-Finnish) · 1/895,263 alleles

Overall 9.11e-05% 1/1,097,848 alleles · very rare

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.Pro549Ser
Coding: c.1645C>T
MANE Select: NM_000044
dbSNP: rs137852588
Type: single nucleotide variant
Location: chrX:67643284 (GRCh38)
Structure: AlphaFold pLDDT 58.85 · 95 PDB
Residue 549: the 'interaction with znf318' region; the 'modulating' region; a UniProt-annotated variant site (in ais)

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

Disease context

hypospadias 1, X-linked — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AR p.Ala871Val Pathogenic/Likely pathogenic ★★ same condition
AR p.Asn757Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
AR p.Val867Met Pathogenic ★★ ⚠ same condition
AR p.Ser176Arg Benign/Likely benign ★★ ⚠ same condition
AR p.Glu204Ter Pathogenic ★ same condition
AR p.Ala385Ser Uncertain significance ★ ⚠ same condition
AR p.Ala475Val Conflicting classifications of pathogenicity ★ ⚠ same condition
AR p.Gln58Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro549ser (accessed [today's date]).

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