Is ADD3 p.Ala261Ser (c.781G>T) pathogenic?

ADD3 p.Ala261Ser (c.781G>T) is classified Uncertain significance in ADD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-21). AlphaMissense: likely benign (0.145); Ultra-rare (popmax 0.0495%, mid).

How common is ADD3 p.Ala261Ser (c.781G>T) in the general population?

ADD3 p.Ala261Ser (c.781G>T) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about ADD3 p.Ala261Ser (c.781G>T)?

AlphaMissense predicts likely benign (score 0.145) — an in-silico prediction, not a clinical call.

ADD3 p.Ala261Ser

c.781G>T · rs764861697 · VCV2377459

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.145 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.145	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -6.43	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 8.6	GERP 0.93, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 33 kb · p 0.53 · regional, not allelic
Overall
CADD	22.4	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 0.0495% Middle Eastern · 3/6,062 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0171%

Overall 0.00285% 46/1,614,120 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,021
South Asian	0.0285%	3,503
Admixed American	0.00666%	15,006
European (non-Finnish)	0.0011%	90,769

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.Ala261Ser
Coding: c.781G>T
MANE Select: NM_016824
dbSNP: rs764861697
Type: single nucleotide variant
Location: chr10:110119274 (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

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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
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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-ala261ser (accessed [today's date]).

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