Is DNHD1 p.Arg2222Cys (c.6664C>T) pathogenic?

DNHD1 p.Arg2222Cys (c.6664C>T) is classified Benign in DNHD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.1524); Low-frequency (popmax 2.39%, afr).

How common is DNHD1 p.Arg2222Cys (c.6664C>T) in the general population?

DNHD1 p.Arg2222Cys (c.6664C>T) is low-frequency (popmax 2.39%, afr) (gnomAD).

What do computational predictors say about DNHD1 p.Arg2222Cys (c.6664C>T)?

AlphaMissense predicts likely benign (score 0.1524) — an in-silico prediction, not a clinical call.

DNHD1 p.Arg2222Cys

c.6664C>T · rs145678295 · VCV776568

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1524 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.39%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.1524	likely benign
REVEL	0.175	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 2.2	GERP 1.9, phastCons 0.98
Regional constraint	o/e 0.90	unconstrained · MANE · 66 kb · p 5.3e-11 · regional, not allelic
Overall
CADD	25.6	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 2.39% African / African-American · 1,743/73,024 alleles

Filtering AF 2.29% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.26%

Overall 0.138% 2,132/1,546,754 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.39%	42
Remaining individualsnot grpmax-eligible	0.251%	399
Admixed American	0.226%	442
Middle Eastern	0.1%	997
South Asian	0.00955%	10,471
European (non-Finnish)	0.00945%	10,586
East Asian	0.00491%	20,369

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.Arg2222Cys
Coding: c.6664C>T
MANE Select: NM_144666
dbSNP: rs145678295
Type: single nucleotide variant
Location: chr11:6547603 (GRCh38)
Gene constraint: LOEUF 0.897 · pLI <0.01 (gnomAD)
Residue 2222: 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.Arg2222His Uncertain significance ★ ⚠ same residue
DNHD1 p.Arg2222Leu 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

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-arg2222cys (accessed [today's date]).

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