Is DNHD1 p.Arg4274Trp (c.12820C>T) pathogenic?

DNHD1 p.Arg4274Trp (c.12820C>T) is classified Uncertain significance in DNHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-11). AlphaMissense: likely benign (0.2747); Ultra-rare (popmax 0.0179%, eas).

How common is DNHD1 p.Arg4274Trp (c.12820C>T) in the general population?

DNHD1 p.Arg4274Trp (c.12820C>T) is ultra-rare (popmax 0.0179%, eas) (gnomAD).

What do computational predictors say about DNHD1 p.Arg4274Trp (c.12820C>T)?

AlphaMissense predicts likely benign (score 0.2747) — an in-silico prediction, not a clinical call.

DNHD1 p.Arg4274Trp

c.12820C>T · rs538629659 · VCV2278147

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2747 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0179%, eas)

Computational evidence

Protein change
AlphaMissense	0.2747	likely benign
REVEL	0.48	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.46	GERP 0.5, phastCons 0.99
Regional constraint	o/e 1.05	unconstrained · MANE · 3,234 bp · p 0.2 · 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

Grpmax group 0.0179% East Asian · 8/44,818 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00642%

Overall 0.00105% 17/1,612,980 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0179%	5,602
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,576
South Asian	0.00331%	30,242
African / African-American	0.00133%	74,988
European (non-Finnish)	0.000339%	294,891

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.Arg4274Trp
Coding: c.12820C>T
MANE Select: NM_144666
dbSNP: rs538629659
Type: single nucleotide variant
Location: chr11:6568823 (GRCh38)
Gene constraint: LOEUF 0.897 · pLI <0.01 (gnomAD)
Residue 4274: a UniProt-annotated variant site (in spgf65); a UniProt-annotated variant site (in spgf65; low expression, if any, in sperm flagella)

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

Similar variants

DNHD1 p.Arg4274Gln Uncertain significance ★ same residue
DNHD1 p.Arg2928Ter Pathogenic/Likely pathogenic ★★ same type
DNHD1 p.Arg3978Ter Pathogenic/Likely pathogenic ★★ same type
DNHD1 p.Arg4048Ter Pathogenic/Likely pathogenic ★★ same type
DNHD1 p.Glu1153Ter Pathogenic/Likely pathogenic ★★ same type
DNHD1 p.Tyr2166Ter Pathogenic/Likely pathogenic ★★ same type
DNHD1 p.Arg1582Trp Uncertain significance ★★ same type
DNHD1 p.Arg1873Ser Uncertain significance ★★ same type

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-arg4274trp (accessed [today's date]).

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