Is DLGAP2 p.Arg658His (c.1973G>A) pathogenic?

DLGAP2 p.Arg658His (c.1973G>A) is classified Uncertain significance in DLGAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-19). AlphaMissense: likely benign (0.0941); Ultra-rare (popmax 0.023%, eas).

How common is DLGAP2 p.Arg658His (c.1973G>A) in the general population?

DLGAP2 p.Arg658His (c.1973G>A) is ultra-rare (popmax 0.023%, eas) (gnomAD).

What do computational predictors say about DLGAP2 p.Arg658His (c.1973G>A)?

AlphaMissense predicts likely benign (score 0.0941) — an in-silico prediction, not a clinical call.

DLGAP2 p.Arg658His

c.1973G>A · VCV3840342

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0941 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.023%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0941	likely benign
REVEL	0.145	moderately benign-leaning
SaProt	LLR -7.40	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 3.5	GERP -0.99, phastCons 1
Overall
CADD	21.7	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R657H vs ClinVar R658H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.023% East Asian · 10/43,472 alleles

Filtering AF 0.0124% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00943%

Overall 0.00232% 37/1,593,162 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.023%	4,347
Middle Eastern	0.0165%	6,068
Admixed American	0.00351%	28,497
Remaining individualsnot grpmax-eligible	0.00324%	30,859
African / African-American	0.00269%	37,135
European (non-Finnish)	0.00162%	61,626
South Asian	0.00114%	87,608

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: DLGAP2
Protein: p.Arg658His
Coding: c.1973G>A
MANE Select: NM_001346810
Type: single nucleotide variant
Location: chr8:1668491 (GRCh38)
Gene constraint: LOEUF 0.425 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 48.83
Residue 658: the 'disordered' region

Full DLGAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DLGAP2 p.Arg658Cys Uncertain significance ★ ⚠ same residue
DLGAP2 p.Arg658= Benign same residue
DLGAP2 c.1810+14A>G Benign ★★ same type
DLGAP2 c.2160+19C>G Benign ★★ same type
DLGAP2 p.Glu678= Benign ★★ same type
DLGAP2 p.Pro464Gln Benign ★★ same type
DLGAP2 c.2203-7G>T Uncertain significance ★ same type
DLGAP2 p.Ala1019Gly 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/dlgap2-p-arg658his (accessed [today's date]).

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