Is ADD3 p.Asp259Val (c.776A>T) pathogenic?

ADD3 p.Asp259Val (c.776A>T) is classified Uncertain significance in ADD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-13). AlphaMissense: ambiguous (0.3988); Ultra-rare (popmax 0.0307%, sas); Associated with complex neurodevelopmental disorder with motor features.

What condition is associated with ADD3 p.Asp259Val (c.776A>T)?

ADD3 p.Asp259Val (c.776A>T) is associated with complex neurodevelopmental disorder with motor features (ClinVar).

How common is ADD3 p.Asp259Val (c.776A>T) in the general population?

ADD3 p.Asp259Val (c.776A>T) is ultra-rare (popmax 0.0307%, sas) (gnomAD).

How is Non-specific syndromic intellectual disability inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ADD3 p.Asp259Val (c.776A>T)?

AlphaMissense predicts ambiguous (score 0.3988) — an in-silico prediction, not a clinical call.

ADD3 p.Asp259Val

c.776A>T · rs55763936 · VCV3082922

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3988 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0307%, sas)

Conditions

complex neurodevelopmental disorder with motor features

Computational evidence

Protein change
AlphaMissense	0.3988	ambiguous
REVEL	0.584	indeterminate
SaProt	LLR -12.33	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 33 kb · p 0.53 · 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 0.0307% South Asian · 28/91,078 alleles

Filtering AF 0.0218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0188%

Overall 0.00186% 30/1,614,042 alleles · ultra-rare exomes 28/1,461,826 · genomes 2/152,216 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0307%	3,253
Remaining individualsnot grpmax-eligible	0.0032%	31,253

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: ADD3
Protein: p.Asp259Val
Coding: c.776A>T
MANE Select: NM_016824
dbSNP: rs55763936
Type: single nucleotide variant
Location: chr10:110119269 (GRCh38)
Gene constraint: LOEUF 0.395 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.83

Full ADD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

complex neurodevelopmental disorder with motor features — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Non-specific syndromic intellectual disability (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Childhood, Infancy

Similar variants

ADD3 p.Asp259Gly Uncertain significance ★★ ⚠ same residue
ADD3 p.Ala588Gly Uncertain significance ★★ ⚠ same condition
ADD3 p.Gly367Asp Pathogenic/Likely pathogenic ★★ same type
ADD3 c.1733-1G>A Uncertain significance ★★ same type
ADD3 p.Arg27Cys Uncertain significance ★★ ⚠ same type
ADD3 p.Arg46Gln Uncertain significance ★★ ⚠ same type
ADD3 p.Arg571His Uncertain significance ★★ ⚠ same type
ADD3 p.Arg645Gln 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/add3-p-asp259val (accessed [today's date]).

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