Is DNHD1 p.Glu3519Ala (c.10556A>C) pathogenic?

DNHD1 p.Glu3519Ala (c.10556A>C) is classified Uncertain significance in DNHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-15). AlphaMissense: likely benign (0.2703); Ultra-rare (popmax 0.015%, afr).

How common is DNHD1 p.Glu3519Ala (c.10556A>C) in the general population?

DNHD1 p.Glu3519Ala (c.10556A>C) is ultra-rare (popmax 0.015%, afr) (gnomAD).

What do computational predictors say about DNHD1 p.Glu3519Ala (c.10556A>C)?

AlphaMissense predicts likely benign (score 0.2703) — an in-silico prediction, not a clinical call.

DNHD1 p.Glu3519Ala

c.10556A>C · rs372025980 · VCV3084668

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2703 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.2703	likely benign
REVEL	0.213	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 9.3	GERP 1.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 66 kb · p 5.3e-11 · regional, not allelic
Overall
CADD	22.2	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 0.015% African / African-American · 11/73,152 alleles

Filtering AF 0.00834% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00647%

Overall 0.000709% 11/1,551,692 alleles · ultra-rare

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.Glu3519Ala
Coding: c.10556A>C
MANE Select: NM_144666
dbSNP: rs372025980
Type: single nucleotide variant
Location: chr11:6564604 (GRCh38)
Gene constraint: LOEUF 0.897 · pLI <0.01 (gnomAD)
Residue 3519: 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.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
DNHD1 p.Arg2555Trp 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-glu3519ala (accessed [today's date]).

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