Is ADD1 p.Val616Ile (c.1846G>A) pathogenic?

ADD1 p.Val616Ile (c.1846G>A) is classified Uncertain significance in ADD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-26). AlphaMissense: likely benign (0.1153); Very rare (popmax 0.00446%, eas).

How common is ADD1 p.Val616Ile (c.1846G>A) in the general population?

ADD1 p.Val616Ile (c.1846G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about ADD1 p.Val616Ile (c.1846G>A)?

AlphaMissense predicts likely benign (score 0.1153) — an in-silico prediction, not a clinical call.

ADD1 p.Val616Ile

c.1846G>A · VCV3269922

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1153 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1153	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -7.03	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 9.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 53 kb · p 0.026 · regional, not allelic
Overall
CADD	26.0	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V554I vs ClinVar V616I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,872 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000496% 8/1,613,938 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,436
Remaining individualsnot grpmax-eligible	0.0016%	62,476
Finnishnot grpmax-eligible	0.00156%	64,038
European (non-Finnish)	0.000339%	294,996

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.Val616Ile
Coding: c.1846G>A
MANE Select: NM_001354761
Type: single nucleotide variant
Location: chr4:2914938 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.73
Residue 616: 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-val616ile (accessed [today's date]).

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