Is DNHD1 p.Arg756His (c.2267G>A) pathogenic?

DNHD1 p.Arg756His (c.2267G>A) is classified Uncertain significance in DNHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-08). AlphaMissense: likely benign (0.0961); Ultra-rare (popmax 0.0415%, eas).

How common is DNHD1 p.Arg756His (c.2267G>A) in the general population?

DNHD1 p.Arg756His (c.2267G>A) is ultra-rare (popmax 0.0415%, eas) (gnomAD).

What do computational predictors say about DNHD1 p.Arg756His (c.2267G>A)?

AlphaMissense predicts likely benign (score 0.0961) — an in-silico prediction, not a clinical call.

DNHD1 p.Arg756His

c.2267G>A · VCV3504131

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0961 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0415%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.0961	likely benign
REVEL	0.072	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.58	GERP -3.9
Regional constraint	o/e 0.90	unconstrained · MANE · 66 kb · p 5.3e-11 · regional, not allelic
Overall
CADD	6.452	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0415% East Asian · 17/40,916 alleles

Filtering AF 0.0264% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0217%

Overall 0.00722% 112/1,551,116 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0415%	2,407
European (non-Finnish)	0.00767%	13,034
Remaining individualsnot grpmax-eligible	0.00666%	15,012
Admixed American	0.00392%	25,508
African / African-American	0.00137%	73,152

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: DNHD1
Protein: p.Arg756His
Coding: c.2267G>A
MANE Select: NM_144666
Type: single nucleotide variant
Location: chr11:6529041 (GRCh38)
Gene constraint: LOEUF 0.897 · pLI <0.01 (gnomAD)

Full DNHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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DNHD1 p.Arg1582Trp Uncertain significance ★★ same type
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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/dnhd1-p-arg756his (accessed [today's date]).

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