Is ADD2 p.Cys282Phe (c.845G>T) pathogenic?

ADD2 p.Cys282Phe (c.845G>T) is classified Uncertain significance in ADD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-10). AlphaMissense: likely pathogenic (0.6125); Very rare (popmax 0.00534%, afr).

How common is ADD2 p.Cys282Phe (c.845G>T) in the general population?

ADD2 p.Cys282Phe (c.845G>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about ADD2 p.Cys282Phe (c.845G>T)?

AlphaMissense predicts likely pathogenic (score 0.6125) — an in-silico prediction, not a clinical call.

ADD2 p.Cys282Phe

c.845G>T · VCV3495543

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6125 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6125	likely pathogenic
REVEL	0.372	indeterminate
SaProt	LLR -10.20	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 21 kb · p 3.2e-07 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00534% African / African-American · 4/74,958 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000931% 15/1,611,736 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,740
Admixed American	0.00337%	29,716
Remaining individualsnot grpmax-eligible	0.0016%	62,404
European (non-Finnish)	0.000678%	147,394

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.Cys282Phe
Coding: c.845G>T
MANE Select: NM_001617
Type: single nucleotide variant
Location: chr2:70690790 (GRCh38)
Gene constraint: LOEUF 0.388 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.51

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-cys282phe (accessed [today's date]).

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