Is DNAH17 p.Ala646Val (c.1937C>T) pathogenic?

DNAH17 p.Ala646Val (c.1937C>T) is classified Uncertain significance in DNAH17 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-29). AlphaMissense: likely benign (0.0903); Very rare (popmax 0.00959%, afr); Associated with Inborn genetic diseases.

What condition is associated with DNAH17 p.Ala646Val (c.1937C>T)?

DNAH17 p.Ala646Val (c.1937C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DNAH17 p.Ala646Val (c.1937C>T) in the general population?

DNAH17 p.Ala646Val (c.1937C>T) is very rare (popmax 0.00959%, afr) (gnomAD).

What do computational predictors say about DNAH17 p.Ala646Val (c.1937C>T)?

AlphaMissense predicts likely benign (score 0.0903) — an in-silico prediction, not a clinical call.

DNAH17 p.Ala646Val

c.1937C>T · VCV4829096

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0903 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00959%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0903	likely benign
REVEL	0.016	strongly 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 -3	GERP -3.2
Regional constraint	o/e 1.09	unconstrained · MANE · 151 kb · p 3.8e-12 · regional, not allelic
Overall
CADD	3.117	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 0.00959% African / African-American · 7/73,006 alleles

Filtering AF 0.00447% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00315%

Overall 0.00155% 24/1,551,594 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00959%	10,429
Admixed American	0.00588%	16,999
East Asian	0.00489%	20,467
Finnishnot grpmax-eligible	0.00335%	29,890
South Asian	0.00119%	84,066
European (non-Finnish)	0.000785%	127,458

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: DNAH17
Protein: p.Ala646Val
Coding: c.1937C>T
MANE Select: NM_173628
Type: single nucleotide variant
Location: chr17:78560834 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Residue 646: a UniProt-annotated variant site (in spgf39); the 'stem' region

Full DNAH17 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DNAH17 p.Ala1014Val Uncertain significance ★★ ⚠ same condition
DNAH17 p.Arg1217Thr Uncertain significance ★★ ⚠ same condition
DNAH17 p.Arg2941Gln Uncertain significance ★★ same condition
DNAH17 p.Arg4050Gln Uncertain significance ★★ same condition
DNAH17 p.Arg4101Gln Uncertain significance ★★ ⚠ same condition
DNAH17 p.Arg4246His Uncertain significance ★★ ⚠ same condition
DNAH17 p.Arg4303Cys Uncertain significance ★★ same condition
DNAH17 p.Asn1230Thr 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/dnah17-p-ala646val (accessed [today's date]).

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