Is DNHD1 p.Pro4257His (c.12770C>A) pathogenic?

DNHD1 p.Pro4257His (c.12770C>A) is classified Conflicting classifications of pathogenicity in DNHD1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-02). AlphaMissense: likely benign (0.0912); Rare (popmax 0.572%, afr).

How common is DNHD1 p.Pro4257His (c.12770C>A) in the general population?

DNHD1 p.Pro4257His (c.12770C>A) is rare (popmax 0.572%, afr) (gnomAD).

What do computational predictors say about DNHD1 p.Pro4257His (c.12770C>A)?

AlphaMissense predicts likely benign (score 0.0912) — an in-silico prediction, not a clinical call.

DNHD1 p.Pro4257His

c.12770C>A · rs138517528 · VCV791309

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0912 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.572%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.0912	likely benign
REVEL	0.154	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 6	GERP 0.56, phastCons 0.81
Regional constraint	o/e 1.05	unconstrained · MANE · 3,234 bp · p 0.2 · regional, not allelic
Overall
CADD	20.7	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 0.572% African / African-American · 429/74,992 alleles

Filtering AF 0.527% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.51%

Overall 0.0302% 488/1,613,534 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.572%	175
Remaining individualsnot grpmax-eligible	0.048%	2,082
Admixed American	0.0233%	4,285
European (non-Finnish)	0.00119%	84,268
South Asian	0.0011%	90,930

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.Pro4257His
Coding: c.12770C>A
MANE Select: NM_144666
dbSNP: rs138517528
Type: single nucleotide variant
Location: chr11:6568773 (GRCh38)
Gene constraint: LOEUF 0.897 · pLI <0.01 (gnomAD)
Residue 4257: 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.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-pro4257his (accessed [today's date]).

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