Is DNHD1 p.Arg4564Pro (c.13691G>C) pathogenic?

DNHD1 p.Arg4564Pro (c.13691G>C) is classified Uncertain significance in DNHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-04). AlphaMissense: ambiguous (0.4738); Ultra-rare (popmax 0.0368%, amr).

How common is DNHD1 p.Arg4564Pro (c.13691G>C) in the general population?

DNHD1 p.Arg4564Pro (c.13691G>C) is ultra-rare (popmax 0.0368%, amr) (gnomAD).

What do computational predictors say about DNHD1 p.Arg4564Pro (c.13691G>C)?

AlphaMissense predicts ambiguous (score 0.4738) — an in-silico prediction, not a clinical call.

DNHD1 p.Arg4564Pro

c.13691G>C · VCV3504117

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4738 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0368%, amr)

Computational evidence

Protein change
AlphaMissense	0.4738	ambiguous
REVEL	0.192	benign-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP -0.7, phastCons 0.88
Regional constraint	o/e 1.05	unconstrained · MANE · 3,234 bp · p 0.2 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0368% Admixed American · 22/59,796 alleles

Filtering AF 0.0249% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.00423% 68/1,606,570 alleles · ultra-rare exomes 58/1,454,234 · genomes 10/152,336 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0368%	2,718
European (non-Finnish)	0.00374%	26,721
Remaining individualsnot grpmax-eligible	0.00322%	31,080

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.Arg4564Pro
Coding: c.13691G>C
MANE Select: NM_144666
Type: single nucleotide variant
Location: chr11:6571203 (GRCh38)
Gene constraint: LOEUF 0.897 · pLI <0.01 (gnomAD)
Residue 4564: 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

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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
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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-arg4564pro (accessed [today's date]).

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