Is ADD2 p.Glu640Lys (c.1918G>A) pathogenic?

ADD2 p.Glu640Lys (c.1918G>A) is classified Uncertain significance in ADD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-04). AlphaMissense: likely benign (0.0708); Rare (popmax 0.148%, mid).

How common is ADD2 p.Glu640Lys (c.1918G>A) in the general population?

ADD2 p.Glu640Lys (c.1918G>A) is rare (popmax 0.148%, mid) (gnomAD).

What do computational predictors say about ADD2 p.Glu640Lys (c.1918G>A)?

AlphaMissense predicts likely benign (score 0.0708) — an in-silico prediction, not a clinical call.

ADD2 p.Glu640Lys

c.1918G>A · VCV3834216

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0708 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.148%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0708	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -7.97	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 0.37	GERP -1.8, phastCons 0.002
Regional constraint	o/e 0.94	unconstrained · MANE · 9,574 bp · p 0.4 · regional, not allelic
Overall
CADD	11.72	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 0.148% Middle Eastern · 9/6,084 alleles

Filtering AF 0.0772% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0576%

Overall 0.00353% 57/1,613,994 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.148%	676
Admixed American	0.00667%	14,999
African / African-American	0.00401%	24,959
European (non-Finnish)	0.0033%	30,257
Remaining individualsnot grpmax-eligible	0.0016%	62,488
South Asian	0.0011%	91,074

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: ADD2
Protein: p.Glu640Lys
Coding: c.1918G>A
MANE Select: NM_001617
Type: single nucleotide variant
Location: chr2:70663688 (GRCh38)
Gene constraint: LOEUF 0.388 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.51
Residue 640: the 'disordered' region

Full ADD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADD2 p.Asp28Asn Benign ★★ ⚠ same type
ADD2 p.Glu335Asp Benign ★★ same type
ADD2 p.Gly17Glu Benign ★★ same type
ADD2 p.Ala150Val Uncertain significance ★ ⚠ same type
ADD2 p.Ala232Gly Uncertain significance ★ ⚠ same type
ADD2 p.Ala312Thr Uncertain significance ★ ⚠ same type
ADD2 p.Ala418Pro Uncertain significance ★ ⚠ same type
ADD2 p.Ala606Val 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/add2-p-glu640lys (accessed [today's date]).

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