Is DDHD1 p.Arg288His (c.863G>A) pathogenic?

DDHD1 p.Arg288His (c.863G>A) is classified Uncertain significance in DDHD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-08). AlphaMissense: likely pathogenic (0.9446); Ultra-rare (popmax 0.0103%, amr); Associated with hereditary spastic paraplegia 28.

What condition is associated with DDHD1 p.Arg288His (c.863G>A)?

DDHD1 p.Arg288His (c.863G>A) is associated with hereditary spastic paraplegia 28 (ClinVar).

How common is DDHD1 p.Arg288His (c.863G>A) in the general population?

DDHD1 p.Arg288His (c.863G>A) is ultra-rare (popmax 0.0103%, amr) (gnomAD).

How is Autosomal recessive spastic paraplegia type 28 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DDHD1 p.Arg288His (c.863G>A)?

AlphaMissense predicts likely pathogenic (score 0.9446) — an in-silico prediction, not a clinical call.

DDHD1 p.Arg288His

c.863G>A · rs904259357 · VCV575789

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9446 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 28

Computational evidence

Protein change
AlphaMissense	0.9446	likely pathogenic
REVEL	0.712	pathogenic-leaning
SaProt	LLR -14.25	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 106 kb · p 7.8e-05 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0103% Admixed American · 6/58,056 alleles

Filtering AF 0.0044% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00303%

Overall 0.00056% 9/1,605,806 alleles · ultra-rare exomes 8/1,453,670 · genomes 1/152,136 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0103%	9,676
European (non-Finnish)	0.000255%	392,512

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: DDHD1
Protein: p.Arg288His
Coding: c.863G>A
MANE Select: NM_001160148
dbSNP: rs904259357
Type: single nucleotide variant
Location: chr14:53103832 (GRCh38)
Gene constraint: LOEUF 0.642 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 67.11

Full DDHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 28 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive spastic paraplegia type 28 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood, Infancy

Similar variants

DDHD1 p.Arg288Cys Uncertain significance ★ ⚠ same residue
DDHD1 p.Ala193Val Uncertain significance ★★ ⚠ same condition
DDHD1 p.Ala94Pro Uncertain significance ★★ ⚠ same condition
DDHD1 p.Arg204Trp Uncertain significance ★★ ⚠ same condition
DDHD1 p.Arg554Gln Uncertain significance ★★ ⚠ same condition
DDHD1 p.Arg570Gln Uncertain significance ★★ ⚠ same condition
DDHD1 p.Arg588Gln Uncertain significance ★★ ⚠ same condition
DDHD1 p.Arg596Gln 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/ddhd1-p-arg288his (accessed [today's date]).

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