Is DHH p.Ala227= (c.681G>T) pathogenic?

DHH p.Ala227= (c.681G>T) is classified Likely benign in DHH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-10). Ultra-rare (popmax 0.0677%, mid); Associated with 46,XY sex reversal 7.

What condition is associated with DHH p.Ala227= (c.681G>T)?

DHH p.Ala227= (c.681G>T) is associated with 46,XY sex reversal 7 (ClinVar).

How common is DHH p.Ala227= (c.681G>T) in the general population?

DHH p.Ala227= (c.681G>T) is ultra-rare (popmax 0.0677%, mid) (gnomAD).

DHH p.Ala227=

c.681G>T · rs746911960 · VCV2051864

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0677%, mid)

Conditions

46,XY sex reversal 7

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.3	GERP -5.6
Overall
CADD	6.521	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0677% Middle Eastern · 4/5,906 alleles

Filtering AF 0.023% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0139%

Overall 0.00205% 33/1,609,328 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0677%	1,477
Remaining individualsnot grpmax-eligible	0.00964%	10,369
South Asian	0.00332%	30,117
European (non-Finnish)	0.00161%	62,031
African / African-American	0.00134%	74,906

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: DHH
Protein: p.Ala227=
Coding: c.681G>T
MANE Select: NM_021044
dbSNP: rs746911960
Type: single nucleotide variant
Location: chr12:49090369 (GRCh38)
Gene constraint: LOEUF 0.999 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.87 · 5 PDB
Residue 227: a UniProt-annotated variant site (in gdmn; uncertain significance); a UniProt-annotated variant site (in gdmn)

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

Disease context

46,XY sex reversal 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DHH p.Ala227Val Pathogenic ★ ⚠ same residue
DHH c.*401G>T Uncertain significance ★★ same condition
DHH p.Ala287Glu Uncertain significance ★★ ⚠ same condition
DHH p.Arg102His Uncertain significance ★★ ⚠ same condition
DHH p.Arg309Leu Uncertain significance ★★ ⚠ same condition
DHH p.Arg318Pro Uncertain significance ★★ ⚠ same condition
DHH p.Ser210Arg Uncertain significance ★★ ⚠ same condition
DHH c.304-15T>C Likely benign ★★ 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/dhh-p-ala227 (accessed [today's date]).

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