Is DHH p.Phe274Leu (c.822T>G) pathogenic?

DHH p.Phe274Leu (c.822T>G) is classified Uncertain significance in DHH (ClinVar, Single submitter, 1 submitter; last evaluated 2019-06-05). AlphaMissense: likely pathogenic (0.9893); Absent from gnomAD v4.1; Associated with 46,XY sex reversal 7.

What condition is associated with DHH p.Phe274Leu (c.822T>G)?

DHH p.Phe274Leu (c.822T>G) is associated with 46,XY sex reversal 7 (ClinVar).

How common is DHH p.Phe274Leu (c.822T>G) in the general population?

DHH p.Phe274Leu (c.822T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DHH p.Phe274Leu (c.822T>G)?

AlphaMissense predicts likely pathogenic (score 0.9893) — an in-silico prediction, not a clinical call.

DHH p.Phe274Leu

c.822T>G · rs1242767279 · VCV948136

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9893 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

46,XY sex reversal 7

Computational evidence

Protein change
AlphaMissense	0.9893	likely pathogenic · top 8% in DHH
REVEL	0.512	indeterminate
SaProt	LLR -6.38	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.36	GERP -3.7, phastCons 0.96
Regional constraint	o/e 0.77	unconstrained · MANE · 4,650 bp · p 8.5e-08 · regional, not allelic
Overall
CADD	23.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DHH
Protein: p.Phe274Leu
Coding: c.822T>G
MANE Select: NM_021044
dbSNP: rs1242767279
Type: single nucleotide variant
Location: chr12:49090228 (GRCh38)
Gene constraint: LOEUF 0.999 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.87 · 5 PDB
Residue 274: 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.Phe274Tyr Uncertain significance ★ ⚠ 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-phe274leu (accessed [today's date]).

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