Is DDHD1 p.Ser93Phe (c.278C>T) pathogenic?

DDHD1 p.Ser93Phe (c.278C>T) is classified Uncertain significance in DDHD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-17). AlphaMissense: ambiguous (0.3459); Very rare (popmax 0.00537%, afr); Associated with Inborn genetic diseases.

What condition is associated with DDHD1 p.Ser93Phe (c.278C>T)?

DDHD1 p.Ser93Phe (c.278C>T) is associated with Inborn genetic diseases, hereditary spastic paraplegia 28 (ClinVar).

How common is DDHD1 p.Ser93Phe (c.278C>T) in the general population?

DDHD1 p.Ser93Phe (c.278C>T) is very rare (popmax 0.00537%, afr) (gnomAD).

What do computational predictors say about DDHD1 p.Ser93Phe (c.278C>T)?

AlphaMissense predicts ambiguous (score 0.3459) — an in-silico prediction, not a clinical call.

DDHD1 p.Ser93Phe

c.278C>T · rs368145864 · VCV1494443

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3459 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00537%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3459	ambiguous
REVEL	0.231	benign-leaning
SaProt	LLR -8.70	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 11	GERP 0.47, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 825 bp · p 0.0075 · regional, not allelic
Overall
CADD	27.8	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 0.00537% African / African-American · 4/74,522 alleles

Filtering AF 0.00402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00362%

Overall 0.00416% 67/1,611,192 alleles · very rare exomes 55/1,460,156 · genomes 12/151,036 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00537%	18,631
European (non-Finnish)	0.00509%	19,655
Remaining individualsnot grpmax-eligible	0.00481%	20,781

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.Ser93Phe
Coding: c.278C>T
MANE Select: NM_001160148
dbSNP: rs368145864
Type: single nucleotide variant
Location: chr14:53152821 (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.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
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-ser93phe (accessed [today's date]).

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