Is DNAH1 p.Phe1664Val (c.4990T>G) pathogenic?

DNAH1 p.Phe1664Val (c.4990T>G) is classified Uncertain significance in DNAH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-07). AlphaMissense: likely pathogenic (0.6839); Ultra-rare (popmax 0.01%, amr); Associated with spermatogenic failure 18.

What condition is associated with DNAH1 p.Phe1664Val (c.4990T>G)?

DNAH1 p.Phe1664Val (c.4990T>G) is associated with spermatogenic failure 18, ciliary dyskinesia, primary, 37 (ClinVar).

How common is DNAH1 p.Phe1664Val (c.4990T>G) in the general population?

DNAH1 p.Phe1664Val (c.4990T>G) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about DNAH1 p.Phe1664Val (c.4990T>G)?

AlphaMissense predicts likely pathogenic (score 0.6839) — an in-silico prediction, not a clinical call.

DNAH1 p.Phe1664Val

c.4990T>G · rs779161859 · VCV2062529

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6839 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

spermatogenic failure 18

Computational evidence

Protein change
AlphaMissense	0.6839	likely pathogenic
REVEL	0.271	benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 42 kb · p 1.9e-16 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/59,964 alleles

Filtering AF 0.00429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00062% 10/1,613,566 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,994
European (non-Finnish)	0.000339%	294,949

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: DNAH1
Protein: p.Phe1664Val
Coding: c.4990T>G
MANE Select: NM_015512
dbSNP: rs779161859
Type: single nucleotide variant
Location: chr3:52362397 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 (gnomAD)
Residue 1664: a UniProt-annotated variant site (in spgf18); the 'aaa 1' region

Full DNAH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spermatogenic failure 18 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ciliary dyskinesia, primary, 37

Similar variants

DNAH1 c.1034-2A>G Likely pathogenic ★★ same condition
DNAH1 c.10474+1G>A Pathogenic/Likely pathogenic ★★ same condition
DNAH1 c.10968+2C>T Likely pathogenic ★★ same condition
DNAH1 c.5244+1G>A Likely pathogenic ★★ same condition
DNAH1 p.Arg1702Ter Pathogenic ★★ same condition
DNAH1 p.Arg2479Ter Pathogenic/Likely pathogenic ★★ same condition
DNAH1 p.Arg2622Ter Pathogenic/Likely pathogenic ★★ same condition
DNAH1 p.Arg2724Ter Pathogenic ★★ 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/dnah1-p-phe1664val (accessed [today's date]).

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