Is DNHD1 p.Ala3963Val (c.11888C>T) pathogenic?

DNHD1 p.Ala3963Val (c.11888C>T) is classified Uncertain significance in DNHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-10). AlphaMissense: likely benign (0.0935); Ultra-rare (popmax 0.0233%, amr).

How common is DNHD1 p.Ala3963Val (c.11888C>T) in the general population?

DNHD1 p.Ala3963Val (c.11888C>T) is ultra-rare (popmax 0.0233%, amr) (gnomAD).

What do computational predictors say about DNHD1 p.Ala3963Val (c.11888C>T)?

AlphaMissense predicts likely benign (score 0.0935) — an in-silico prediction, not a clinical call.

DNHD1 p.Ala3963Val

c.11888C>T · rs767851084 · VCV2355776

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0935 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0233%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.0935	likely benign
REVEL	0.04	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 4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 3,984 bp · p 0.00012 · regional, not allelic
Overall
CADD	18.31	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 0.0233% Admixed American · 14/59,962 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.000992% 16/1,613,636 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0233%	4,283
Remaining individualsnot grpmax-eligible	0.0032%	31,230

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.Ala3963Val
Coding: c.11888C>T
MANE Select: NM_144666
dbSNP: rs767851084
Type: single nucleotide variant
Location: chr11:6567397 (GRCh38)
Gene constraint: LOEUF 0.897 · pLI <0.01 (gnomAD)
Residue 3963: 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-ala3963val (accessed [today's date]).

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