Is DDI2 p.Phe88Leu (c.264C>G) pathogenic?

DDI2 p.Phe88Leu (c.264C>G) is classified Uncertain significance in DDI2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: ambiguous (0.5596); Very rare (popmax 0.00941%, nfe).

How common is DDI2 p.Phe88Leu (c.264C>G) in the general population?

DDI2 p.Phe88Leu (c.264C>G) is very rare (popmax 0.00941%, nfe) (gnomAD).

What do computational predictors say about DDI2 p.Phe88Leu (c.264C>G)?

AlphaMissense predicts ambiguous (score 0.5596) — an in-silico prediction, not a clinical call.

DDI2 p.Phe88Leu

c.264C>G · VCV4010013

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5596 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00941%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5596	ambiguous
REVEL	0.11	moderately benign-leaning
SaProt	LLR -5.06	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -0.66, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 16 kb · p 1.3e-08 · regional, not allelic
Overall
CADD	18.51	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 0.00941% European (non-Finnish) · 111/1,180,026 alleles

Filtering AF 0.00791% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00744%

Overall 0.00713% 115/1,613,918 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00941%	10,631
Remaining individualsnot grpmax-eligible	0.0048%	20,827
African / African-American	0.00134%	74,874

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: DDI2
Protein: p.Phe88Leu
Coding: c.264C>G
MANE Select: NM_032341
Type: single nucleotide variant
Location: chr1:15626794 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.85 · 3 PDB

Full DDI2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DDI2 p.Ala394Pro Uncertain significance ★ ⚠ same type
DDI2 p.Arg108Gln Uncertain significance ★ ⚠ same type
DDI2 p.Arg108Trp Uncertain significance ★ ⚠ same type
DDI2 p.Arg110His Uncertain significance ★ ⚠ same type
DDI2 p.Arg139Ter Uncertain significance ★ same type
DDI2 p.Arg173Gly Uncertain significance ★ ⚠ same type
DDI2 p.Arg184Gln Uncertain significance ★ ⚠ same type
DDI2 p.Arg277Gln Uncertain significance ★ ⚠ same type

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/ddi2-p-phe88leu (accessed [today's date]).

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