Is DNHD1 p.Ala657Ser (c.1969G>T) pathogenic?

DNHD1 p.Ala657Ser (c.1969G>T) is classified Uncertain significance in DNHD1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-11-29). AlphaMissense: likely benign (0.0834); Very rare (popmax 7.15e-05%); Associated with DNHD1-related disorder.

What condition is associated with DNHD1 p.Ala657Ser (c.1969G>T)?

DNHD1 p.Ala657Ser (c.1969G>T) is associated with DNHD1-related disorder (ClinVar).

How common is DNHD1 p.Ala657Ser (c.1969G>T) in the general population?

DNHD1 p.Ala657Ser (c.1969G>T) is very rare (popmax 7.15e-05%) (gnomAD).

What do computational predictors say about DNHD1 p.Ala657Ser (c.1969G>T)?

AlphaMissense predicts likely benign (score 0.0834) — an in-silico prediction, not a clinical call.

DNHD1 p.Ala657Ser

c.1969G>T · rs2494007047 · VCV3044163

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0834 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 7.15e-05%)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

DNHD1-related disorder

Computational evidence

Protein change
AlphaMissense	0.0834	likely benign
REVEL	0.005	strongly benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	Δ0.47	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -0.072	GERP -3.8
Regional constraint	o/e 0.90	unconstrained · MANE · 66 kb · p 5.3e-11 · regional, not allelic
Overall
CADD	11.23	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 7.15e-05%

Overall 7.15e-05% 1/1,399,400 alleles · very 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.Ala657Ser
Coding: c.1969G>T
MANE Select: NM_144666
dbSNP: rs2494007047
Type: single nucleotide variant
Location: chr11:6528653 (GRCh38)
Gene constraint: LOEUF 0.897 · pLI <0.01 (gnomAD)

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

Disease context

DNHD1-related disorder

Similar variants

DNHD1 p.Glu4486Lys Uncertain significance ★★ ⚠ same condition
DNHD1 p.His4162Leu Uncertain significance ★★ ⚠ same condition
DNHD1 p.Arg2840Gln Uncertain significance ★ ⚠ same condition
DNHD1 p.Gln895Ter Conflicting classifications of pathogenicity ★ same condition
DNHD1 p.His3335Arg Uncertain significance ★ ⚠ same condition
DNHD1 p.Glu971Lys Uncertain significance same condition
DNHD1 p.Met1535Val Uncertain significance ⚠ same condition
DNHD1 p.Ser920Gly Uncertain significance ⚠ same condition

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-ala657ser (accessed [today's date]).

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