Is ADD1 p.Val305Met (c.913G>A) pathogenic?

ADD1 p.Val305Met (c.913G>A) is classified Uncertain significance in ADD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-11). AlphaMissense: ambiguous (0.4001); Very rare (popmax 0.00898%, nfe).

How common is ADD1 p.Val305Met (c.913G>A) in the general population?

ADD1 p.Val305Met (c.913G>A) is very rare (popmax 0.00898%, nfe) (gnomAD).

What do computational predictors say about ADD1 p.Val305Met (c.913G>A)?

AlphaMissense predicts ambiguous (score 0.4001) — an in-silico prediction, not a clinical call.

ADD1 p.Val305Met

c.913G>A · VCV3834099

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4001 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00898%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4001	ambiguous
REVEL	0.346	indeterminate
SaProt	LLR -14.64	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.85, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 53 kb · p 0.026 · regional, not allelic
Overall
CADD	27.6	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 0.00898% European (non-Finnish) · 106/1,180,050 alleles

Filtering AF 0.00757% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00706%

Overall 0.00743% 120/1,614,202 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0096%	10,419
European (non-Finnish)grpmax	0.00898%	11,133
African / African-American	0.008%	12,506
East Asian	0.00223%	44,884
Admixed American	0.00167%	60,028

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val305Met
Coding: c.913G>A
MANE Select: NM_001354761
Type: single nucleotide variant
Location: chr4:2898460 (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 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-val305met (accessed [today's date]).

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