Is ADD2 p.Pro694Ala (c.2080C>G) pathogenic?

ADD2 p.Pro694Ala (c.2080C>G) is classified Uncertain significance in ADD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: ambiguous (0.3529); Very rare (popmax 0.005%, nfe).

How common is ADD2 p.Pro694Ala (c.2080C>G) in the general population?

ADD2 p.Pro694Ala (c.2080C>G) is very rare (popmax 0.005%, nfe) (gnomAD).

What do computational predictors say about ADD2 p.Pro694Ala (c.2080C>G)?

AlphaMissense predicts ambiguous (score 0.3529) — an in-silico prediction, not a clinical call.

ADD2 p.Pro694Ala

c.2080C>G · rs915495246 · VCV2328960

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3529 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3529	ambiguous
REVEL	0.159	moderately benign-leaning
SaProt	LLR -5.49	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 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 9,574 bp · p 0.4 · regional, not allelic
Overall
CADD	25.1	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 0.005% European (non-Finnish) · 59/1,180,016 alleles

Filtering AF 0.00394% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00361%

Overall 0.00372% 60/1,613,936 alleles · very rare exomes 51/1,461,884 · genomes 9/152,052 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.005%	20,000
Admixed American	0.00167%	60,004

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.Pro694Ala
Coding: c.2080C>G
MANE Select: NM_001617
dbSNP: rs915495246
Type: single nucleotide variant
Location: chr2:70663526 (GRCh38)
Gene constraint: LOEUF 0.388 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.51
Residue 694: 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-pro694ala (accessed [today's date]).

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