Is ADD1 p.Val559Met (c.1675G>A) pathogenic?

ADD1 p.Val559Met (c.1675G>A) is classified Benign in ADD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.075); Low-frequency (popmax 1.1%, afr).

How common is ADD1 p.Val559Met (c.1675G>A) in the general population?

ADD1 p.Val559Met (c.1675G>A) is low-frequency (popmax 1.1%, afr) (gnomAD).

What do computational predictors say about ADD1 p.Val559Met (c.1675G>A)?

AlphaMissense predicts likely benign (score 0.075) — an in-silico prediction, not a clinical call.

ADD1 p.Val559Met

c.1675G>A · rs146536048 · VCV710319

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.075 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.1%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.075	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -7.42	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 1.3	GERP 0.67, phastCons 0.7
Regional constraint	o/e 0.93	unconstrained · MANE · 53 kb · p 0.026 · regional, not allelic
Overall
CADD	15.63	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V528M vs ClinVar V559M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.1% African / African-American · 823/75,072 alleles

Filtering AF 1.03% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.01%

Overall 0.315% 5,080/1,614,254 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.1%	91
Middle Eastern	0.94%	106
South Asian	0.48%	208
Remaining individualsnot grpmax-eligible	0.402%	249
Admixed American	0.302%	332
European (non-Finnish)	0.279%	359
Finnishnot grpmax-eligible	0.0484%	2,066
Ashkenazi Jewishnot grpmax-eligible	0.0304%	3,290
East Asian	0.00223%	44,888

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: ADD1
Protein: p.Val559Met
Coding: c.1675G>A
MANE Select: NM_001354761
dbSNP: rs146536048
Type: single nucleotide variant
Location: chr4:2908581 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.73

Full ADD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADD1 p.Val234= Benign ★★ same type
ADD1 c.2047+530G>A Uncertain significance ★ same type
ADD1 c.2047+541G>T Uncertain significance ★ same type
ADD1 p.Ala137Val Uncertain significance ★ ⚠ same type
ADD1 p.Ala151Thr Uncertain significance ★ ⚠ same type
ADD1 p.Ala156Thr Uncertain significance ★ ⚠ same type
ADD1 p.Ala18Thr Uncertain significance ★ same type
ADD1 p.Ala194Val 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/add1-p-val559met (accessed [today's date]).

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