Is DLGAP5 p.Ile656Phe (c.1966A>T) pathogenic?

DLGAP5 p.Ile656Phe (c.1966A>T) is classified Uncertain significance in DLGAP5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-23). AlphaMissense: likely benign (0.062); Very rare (popmax 0.00331%, nfe).

How common is DLGAP5 p.Ile656Phe (c.1966A>T) in the general population?

DLGAP5 p.Ile656Phe (c.1966A>T) is very rare (popmax 0.00331%, nfe) (gnomAD).

What do computational predictors say about DLGAP5 p.Ile656Phe (c.1966A>T)?

AlphaMissense predicts likely benign (score 0.062) — an in-silico prediction, not a clinical call.

DLGAP5 p.Ile656Phe

c.1966A>T · VCV3840366

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.062 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00331%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.062	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -6.69	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.3	GERP 0.81, phastCons 0.4
Regional constraint	o/e 1.05	unconstrained · MANE · 41 kb · p 0.094 · regional, not allelic
Overall
CADD	9.508	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 0.00331% European (non-Finnish) · 39/1,179,982 alleles

Filtering AF 0.00247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00254% 41/1,614,008 alleles · very rare exomes 38/1,461,796 · genomes 3/152,212 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00331%	30,256
Finnishnot grpmax-eligible	0.00312%	32,022

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: DLGAP5
Protein: p.Ile656Phe
Coding: c.1966A>T
MANE Select: NM_014750
Type: single nucleotide variant
Location: chr14:55154714 (GRCh38)
Gene constraint: LOEUF 1.112 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 56.52 · 4 PDB
Residue 656: the 'disordered' region

Full DLGAP5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DLGAP5 p.Ile656Val Uncertain significance ★ ⚠ same residue
DLG1 p.His120Arg Uncertain significance ★★ ⚠ same type
DLG1 p.Ala262= Benign ★★ same type
DLG1 p.Asp633Glu Benign ★★ same type
DLG1 p.Ser470= Benign ★★ same type
DLG1 p.Val167= Benign ★★ same type
DLGAP5 c.1049+7A>C Benign ★★ same type
DLGAP5 c.2064-1G>A Likely pathogenic ★ 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/dlgap5-p-ile656phe (accessed [today's date]).

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