Is DDHD1 p.Pro127Ala (c.379C>G) pathogenic?

DDHD1 p.Pro127Ala (c.379C>G) is classified Uncertain significance in DDHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-17). AlphaMissense: likely benign (0.0554); Very rare (popmax 0.00843%, amr); Associated with hereditary spastic paraplegia 28.

What condition is associated with DDHD1 p.Pro127Ala (c.379C>G)?

DDHD1 p.Pro127Ala (c.379C>G) is associated with hereditary spastic paraplegia 28 (ClinVar).

How common is DDHD1 p.Pro127Ala (c.379C>G) in the general population?

DDHD1 p.Pro127Ala (c.379C>G) is very rare (popmax 0.00843%, 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.Pro127Ala (c.379C>G)?

AlphaMissense predicts likely benign (score 0.0554) — an in-silico prediction, not a clinical call.

DDHD1 p.Pro127Ala

c.379C>G · rs765734579 · VCV2150152

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0554 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00843%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 28

Computational evidence

Protein change
AlphaMissense	0.0554	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -6.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.66	GERP -2, phastCons 0.013
Regional constraint	o/e 1.13	unconstrained · MANE · 825 bp · p 0.0075 · regional, not allelic
Overall
CADD	12.36	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00843% Admixed American · 5/59,294 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00209%

Overall 0.000374% 6/1,605,252 alleles · very rare exomes 5/1,454,850 · genomes 1/150,402 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00843%	11,859
African / African-American	0.00135%	74,302

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.Pro127Ala
Coding: c.379C>G
MANE Select: NM_001160148
dbSNP: rs765734579
Type: single nucleotide variant
Location: chr14:53152720 (GRCh38)
Gene constraint: LOEUF 0.642 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 67.11
Residue 127: the 'disordered' region

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.Pro127= Likely benign ★ 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.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

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-pro127ala (accessed [today's date]).

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