Is DNHD1 p.Ala1552Ser (c.4654G>T) pathogenic?

DNHD1 p.Ala1552Ser (c.4654G>T) is classified Uncertain significance in DNHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-17). AlphaMissense: likely benign (0.0799); Rare (popmax 0.175%, nfe).

How common is DNHD1 p.Ala1552Ser (c.4654G>T) in the general population?

DNHD1 p.Ala1552Ser (c.4654G>T) is rare (popmax 0.175%, nfe) (gnomAD).

What do computational predictors say about DNHD1 p.Ala1552Ser (c.4654G>T)?

AlphaMissense predicts likely benign (score 0.0799) — an in-silico prediction, not a clinical call.

DNHD1 p.Ala1552Ser

c.4654G>T · rs200223989 · VCV2377109

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0799 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.175%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.0799	likely benign
REVEL	0.046	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 1.7	GERP -1.5, phastCons 0.015
Regional constraint	o/e 0.90	unconstrained · MANE · 66 kb · p 5.3e-11 · regional, not allelic
Overall
CADD	6.067	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 0.175% European (non-Finnish) · 2,013/1,147,048 alleles

Filtering AF 0.169% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.167%

Overall 0.134% 2,082/1,551,980 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.175%	570
Remaining individualsnot grpmax-eligible	0.0582%	1,720
Finnishnot grpmax-eligible	0.0233%	4,288
African / African-American	0.0191%	5,226
Admixed American	0.0118%	8,502

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.Ala1552Ser
Coding: c.4654G>T
MANE Select: NM_144666
dbSNP: rs200223989
Type: single nucleotide variant
Location: chr11:6545593 (GRCh38)
Gene constraint: LOEUF 0.897 · pLI <0.01 (gnomAD)
Residue 1552: a UniProt-annotated variant site (in spgf65)

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-ala1552ser (accessed [today's date]).

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