Is ADD3 p.Asp418Val (c.1253A>T) pathogenic?

ADD3 p.Asp418Val (c.1253A>T) is classified Uncertain significance in ADD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: likely benign (0.3003); Very rare (popmax 0.00119%, nfe).

How common is ADD3 p.Asp418Val (c.1253A>T) in the general population?

ADD3 p.Asp418Val (c.1253A>T) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about ADD3 p.Asp418Val (c.1253A>T)?

AlphaMissense predicts likely benign (score 0.3003) — an in-silico prediction, not a clinical call.

ADD3 p.Asp418Val

c.1253A>T · VCV4638049

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3003 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3003	likely benign
REVEL	0.304	indeterminate
SaProt	LLR -7.79	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 33 kb · p 0.53 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00119% European (non-Finnish) · 14/1,180,014 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000958% 14/1,461,872 alleles · very rare

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.Asp418Val
Coding: c.1253A>T
MANE Select: NM_016824
Type: single nucleotide variant
Location: chr10:110124126 (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

Similar variants

ADD3 p.Asp418Asn Uncertain significance ★ ⚠ same residue
ADD3 p.Gly367Asp Pathogenic/Likely pathogenic ★★ same type
ADD3 c.1733-1G>A Uncertain significance ★★ same type
ADD3 p.Ala588Gly 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-asp418val (accessed [today's date]).

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