Is AR p.Arg616His (c.1847G>A) pathogenic?

AR p.Arg616His (c.1847G>A) is classified Pathogenic in AR (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-22). AlphaMissense: likely pathogenic (0.9998); Very rare (popmax 0.000112%, nfe); Associated with androgen insensitivity syndrome.

What condition is associated with AR p.Arg616His (c.1847G>A)?

AR p.Arg616His (c.1847G>A) is associated with androgen insensitivity syndrome, partial androgen insensitivity syndrome, Kennedy disease (ClinVar).

How common is AR p.Arg616His (c.1847G>A) in the general population?

AR p.Arg616His (c.1847G>A) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about AR p.Arg616His (c.1847G>A)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

AR p.Arg616His

c.1847G>A · rs754201976 · VCV279684

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

androgen insensitivity syndrome

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic ✓ concordant with ClinVar · top 4% in AR
REVEL	0.981	strongly pathogenic-leaning
SaProt	LLR -14.49	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Overall
CADD	31.0	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 0.000112% European (non-Finnish) · 1/894,957 alleles

Overall 8.26e-05% 1/1,210,890 alleles · very rare exomes 1/1,097,401 · genomes 0/113,489 · joint denominator

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.Arg616His
Coding: c.1847G>A
MANE Select: NM_000044
dbSNP: rs754201976
Type: single nucleotide variant
Location: chrX:67686088 (GRCh38)
Structure: AlphaFold pLDDT 58.85 · 95 PDB
Residue 616: the 'interaction with hipk3' region; the 'interaction with ccar1' region; a DNA-binding region; an α-helix; the 'interaction with lpxn' region; a UniProt-annotated variant site (in ais and pais); a UniProt-annotated variant site (in ais)

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

Disease context

androgen insensitivity syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: partial androgen insensitivity syndrome Kennedy disease

Similar variants

AR p.Arg616Cys Pathogenic/Likely pathogenic ★★ 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-arg616his (accessed [today's date]).

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