Is DHH p.His181= (c.543C>T) pathogenic?

DHH p.His181= (c.543C>T) is classified Benign in DHH (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-03). Low-frequency (popmax 2.51%, sas); Associated with 46,XY sex reversal 7.

What condition is associated with DHH p.His181= (c.543C>T)?

DHH p.His181= (c.543C>T) is associated with 46,XY sex reversal 7 (ClinVar).

How common is DHH p.His181= (c.543C>T) in the general population?

DHH p.His181= (c.543C>T) is low-frequency (popmax 2.51%, sas) (gnomAD).

DHH p.His181=

c.543C>T · rs117527954 · VCV309103

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.51%, sas)

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	<0.2	all four deltas below 0.2 · G>C here scores Δ0.53 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.57	GERP -1.5, phastCons 0.99
Overall
CADD	12.51	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.51% South Asian · 2,286/91,082 alleles

Filtering AF 2.42% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.39%

Overall 1.08% 17,450/1,614,248 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	2.51%	40
Finnishnot grpmax-eligible	1.23%	81
European (non-Finnish)	1.12%	89
Middle Eastern	0.973%	103
Remaining individualsnot grpmax-eligible	0.933%	107
Admixed American	0.595%	168
African / African-American	0.177%	564
Ashkenazi Jewishnot grpmax-eligible	0.135%	740
East Asian	0.00668%	14,963

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.His181=
Coding: c.543C>T
MANE Select: NM_021044
dbSNP: rs117527954
Type: single nucleotide variant
Location: chr12:49091150 (GRCh38)
Gene constraint: LOEUF 0.999 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.87 · 5 PDB
Residue 181: a UniProt-annotated variant site (in gdmn; uncertain significance); a β-strand

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 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
DHH c.-255T>C 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-his181 (accessed [today's date]).

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