Is DHH p.Ser210Arg (c.630C>A) pathogenic?

DHH p.Ser210Arg (c.630C>A) is classified Uncertain significance in DHH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-26). AlphaMissense: likely pathogenic (0.586); Ultra-rare (popmax 0.0117%, amr); Associated with 46,XY sex reversal 7.

What condition is associated with DHH p.Ser210Arg (c.630C>A)?

DHH p.Ser210Arg (c.630C>A) is associated with 46,XY sex reversal 7 (ClinVar).

How common is DHH p.Ser210Arg (c.630C>A) in the general population?

DHH p.Ser210Arg (c.630C>A) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about DHH p.Ser210Arg (c.630C>A)?

AlphaMissense predicts likely pathogenic (score 0.586) — an in-silico prediction, not a clinical call.

DHH p.Ser210Arg

c.630C>A · rs764922471 · VCV881976

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.586 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

46,XY sex reversal 7

Computational evidence

Protein change
AlphaMissense	0.586	likely pathogenic
REVEL	0.494	indeterminate
SaProt	LLR -9.95	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.4	GERP 0.82, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 4,650 bp · p 8.5e-08 · regional, not allelic
Overall
CADD	18.37	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 0.0117% Admixed American · 7/59,718 alleles

Filtering AF 0.00546% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00382%

Overall 0.000622% 10/1,608,844 alleles · ultra-rare exomes 8/1,456,642 · genomes 2/152,202 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,531
Remaining individualsnot grpmax-eligible	0.00161%	62,300
European (non-Finnish)	0.00017%	589,616

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.Ser210Arg
Coding: c.630C>A
MANE Select: NM_021044
dbSNP: rs764922471
Type: single nucleotide variant
Location: chr12:49090420 (GRCh38)
Gene constraint: LOEUF 0.999 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.87 · 5 PDB
Residue 210: 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 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 c.304-15T>C Likely benign ★★ same condition
DHH c.-255T>C Benign ★★ same condition
DHH c.*219G>A 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-ser210arg (accessed [today's date]).

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