Is ADD1 p.Val10Met (c.28G>A) pathogenic?

ADD1 p.Val10Met (c.28G>A) is classified Uncertain significance in ADD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). AlphaMissense: ambiguous (0.3497); Ultra-rare (popmax 0.0125%, nfe).

How common is ADD1 p.Val10Met (c.28G>A) in the general population?

ADD1 p.Val10Met (c.28G>A) is ultra-rare (popmax 0.0125%, nfe) (gnomAD).

What do computational predictors say about ADD1 p.Val10Met (c.28G>A)?

AlphaMissense predicts ambiguous (score 0.3497) — an in-silico prediction, not a clinical call.

ADD1 p.Val10Met

c.28G>A · rs773145477 · VCV2469032

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3497 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0125%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3497	ambiguous
REVEL	0.186	benign-leaning
SaProt	LLR -7.53	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 9.6	GERP 0.49, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 53 kb · p 0.026 · regional, not allelic
Overall
CADD	28.7	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 0.0125% European (non-Finnish) · 147/1,178,794 alleles

Filtering AF 0.0108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.00931% 150/1,610,640 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0125%	8,019
African / African-American	0.00267%	37,386
Remaining individualsnot grpmax-eligible	0.0016%	62,338

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.Val10Met
Coding: c.28G>A
MANE Select: NM_001354761
dbSNP: rs773145477
Type: single nucleotide variant
Location: chr4:2875943 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.73
Residue 10: the 'disordered' region

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

Similar variants

ADD1 p.Val234= Benign ★★ same type
ADD1 p.Val559Met 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

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-val10met (accessed [today's date]).

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