Is DDHD2 p.Pro18Leu (c.53C>T) pathogenic?

DDHD2 p.Pro18Leu (c.53C>T) is classified Uncertain significance in DDHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-28). AlphaMissense: likely benign (0.0654); Very rare (popmax 0.004%, afr); Associated with Inborn genetic diseases.

What condition is associated with DDHD2 p.Pro18Leu (c.53C>T)?

DDHD2 p.Pro18Leu (c.53C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DDHD2 p.Pro18Leu (c.53C>T) in the general population?

DDHD2 p.Pro18Leu (c.53C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about DDHD2 p.Pro18Leu (c.53C>T)?

AlphaMissense predicts likely benign (score 0.0654) — an in-silico prediction, not a clinical call.

DDHD2 p.Pro18Leu

c.53C>T · VCV4009990

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0654 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0654	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -6.47	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 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 21 kb · p 0.01 · regional, not allelic
Overall
CADD	23.2	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 0.004% African / African-American · 3/74,928 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00062% 10/1,614,072 alleles · very rare exomes 8/1,461,874 · genomes 2/152,198 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,976
Admixed American	0.00333%	29,995
Remaining individualsnot grpmax-eligible	0.0016%	62,490
South Asian	0.0011%	91,088
European (non-Finnish)	0.000254%	393,349

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: DDHD2
Protein: p.Pro18Leu
Coding: c.53C>T
MANE Select: NM_015214
Type: single nucleotide variant
Location: chr8:38233047 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70
Residue 18: the 'disordered' region

Full DDHD2 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

Similar variants

DDHD2 p.Pro18Ala Uncertain significance ★ ⚠ same residue
PLPP5 p.Leu18Phe Uncertain significance ★ ⚠ same residue
DDHD2 p.Asp660His Pathogenic/Likely pathogenic ★★ same condition
DDHD2 p.Arg232Gln Uncertain significance ★★ ⚠ same condition
DDHD2 p.Arg329Gln Uncertain significance ★★ ⚠ same condition
DDHD2 p.Arg494Gln Uncertain significance ★★ ⚠ same condition
DDHD2 p.Arg494Trp Uncertain significance ★★ ⚠ same condition
DDHD2 p.Arg595Gln 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/ddhd2-p-pro18leu (accessed [today's date]).

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