Is DDHD1 p.Ala94Pro (c.280G>C) pathogenic?

DDHD1 p.Ala94Pro (c.280G>C) is classified Uncertain significance in DDHD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-28). AlphaMissense: ambiguous (0.3646); Very rare (popmax 0.00939%, afr); Associated with Inborn genetic diseases.

What condition is associated with DDHD1 p.Ala94Pro (c.280G>C)?

DDHD1 p.Ala94Pro (c.280G>C) is associated with Inborn genetic diseases, hereditary spastic paraplegia 28 (ClinVar).

How common is DDHD1 p.Ala94Pro (c.280G>C) in the general population?

DDHD1 p.Ala94Pro (c.280G>C) is very rare (popmax 0.00939%, afr) (gnomAD).

What do computational predictors say about DDHD1 p.Ala94Pro (c.280G>C)?

AlphaMissense predicts ambiguous (score 0.3646) — an in-silico prediction, not a clinical call.

DDHD1 p.Ala94Pro

c.280G>C · rs758060048 · VCV464310

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3646 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00939%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3646	ambiguous
REVEL	0.199	benign-leaning
SaProt	LLR -5.54	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 1.3, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 825 bp · p 0.0075 · regional, not allelic
Overall
CADD	25.4	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 0.00939% African / African-American · 7/74,546 alleles

Filtering AF 0.00439% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.0031% 50/1,611,130 alleles · very rare exomes 43/1,459,966 · genomes 7/151,164 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00939%	10,649
Admixed American	0.00501%	19,959
European (non-Finnish)	0.00322%	31,034
Remaining individualsnot grpmax-eligible	0.00321%	31,169

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.Ala94Pro
Coding: c.280G>C
MANE Select: NM_001160148
dbSNP: rs758060048
Type: single nucleotide variant
Location: chr14:53152819 (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

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

Also linked: hereditary spastic paraplegia 28

Similar variants

DDHD1 p.Ala94= Likely benign ★ same residue
DDHD1 p.Ala193Val Uncertain significance ★★ ⚠ same condition
DDHD1 p.Arg204Trp Uncertain significance ★★ ⚠ same condition
DDHD1 p.Arg288His 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-ala94pro (accessed [today's date]).

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