Is DNHD1 p.Pro2755Ser (c.8263C>T) pathogenic?

DNHD1 p.Pro2755Ser (c.8263C>T) is classified Benign in DNHD1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-15). AlphaMissense: likely benign (0.0881); Common (popmax 7.24%, sas) — too common for a highly-penetrant pathogenic allele; Associated with DNHD1-related disorder.

What condition is associated with DNHD1 p.Pro2755Ser (c.8263C>T)?

DNHD1 p.Pro2755Ser (c.8263C>T) is associated with DNHD1-related disorder (ClinVar).

What do computational predictors say about DNHD1 p.Pro2755Ser (c.8263C>T)?

AlphaMissense predicts likely benign (score 0.0881) — an in-silico prediction, not a clinical call.

DNHD1 p.Pro2755Ser

Q: How common is DNHD1 p.Pro2755Ser (c.8263C>T) in the general population?

DNHD1 p.Pro2755Ser (c.8263C>T) is common (popmax 7.24%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.8263C>T · rs111982303 · VCV3056370

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0881 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.24%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

DNHD1-related disorder

Computational evidence

Protein change
AlphaMissense	0.0881	likely benign
REVEL	0.012	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 -0.58	GERP -3.2
Regional constraint	o/e 0.90	unconstrained · MANE · 66 kb · p 5.3e-11 · regional, not allelic
Overall
CADD	0.116	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 7.24% South Asian · 6,082/84,056 alleles

Filtering AF 7.08% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.02%

Overall 0.969% 15,034/1,551,652 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	7.24%	14
Middle Eastern	1.82%	55
Admixed American	1.68%	59
East Asian	1.42%	70
Remaining individualsnot grpmax-eligible	1.24%	81
African / African-American	0.866%	116
Ashkenazi Jewishnot grpmax-eligible	0.548%	182
Finnishnot grpmax-eligible	0.503%	199
European (non-Finnish)	0.485%	206

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.Pro2755Ser
Coding: c.8263C>T
MANE Select: NM_144666
dbSNP: rs111982303
Type: single nucleotide variant
Location: chr11:6557558 (GRCh38)
Gene constraint: LOEUF 0.897 · pLI <0.01 (gnomAD)
Residue 2755: the 'disordered' region; 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

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.Ala657Ser Uncertain significance ⚠ same condition
DNHD1 p.Glu971Lys Uncertain significance ⚠ same condition
DNHD1 p.Met1535Val 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-pro2755ser (accessed [today's date]).

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