Is ADD3 p.Met538Val (c.1612A>G) pathogenic?

ADD3 p.Met538Val (c.1612A>G) is classified Uncertain significance in ADD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). AlphaMissense: likely benign (0.0658); Very rare (popmax 0.00769%, sas).

How common is ADD3 p.Met538Val (c.1612A>G) in the general population?

ADD3 p.Met538Val (c.1612A>G) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about ADD3 p.Met538Val (c.1612A>G)?

AlphaMissense predicts likely benign (score 0.0658) — an in-silico prediction, not a clinical call.

ADD3 p.Met538Val

c.1612A>G · VCV4638048

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0658 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0658	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -4.58	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 9.2	GERP 2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 33 kb · p 0.53 · regional, not allelic
Overall
CADD	16.98	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 0.00769% South Asian · 7/91,034 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00136% 22/1,613,640 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00769%	13,005
Admixed American	0.00334%	29,974
Remaining individualsnot grpmax-eligible	0.0016%	62,460
African / African-American	0.00133%	74,918
European (non-Finnish)	0.000932%	107,259

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.Met538Val
Coding: c.1612A>G
MANE Select: NM_016824
Type: single nucleotide variant
Location: chr10:110130366 (GRCh38)
Gene constraint: LOEUF 0.395 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.83
Residue 538: the 'disordered' region

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

Similar variants

ADD3 p.Met538Leu 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-met538val (accessed [today's date]).

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