Is AADAC p.Phe376Leu (c.1126T>C) pathogenic?

AADAC p.Phe376Leu (c.1126T>C) is classified Uncertain significance in AADAC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-22). AlphaMissense: ambiguous (0.3489); Ultra-rare (popmax 0.029%, eas).

How common is AADAC p.Phe376Leu (c.1126T>C) in the general population?

AADAC p.Phe376Leu (c.1126T>C) is ultra-rare (popmax 0.029%, eas) (gnomAD).

What do computational predictors say about AADAC p.Phe376Leu (c.1126T>C)?

AlphaMissense predicts ambiguous (score 0.3489) — an in-silico prediction, not a clinical call.

AADAC p.Phe376Leu

c.1126T>C · rs187652875 · VCV2592546

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3489 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.029%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3489	ambiguous
REVEL	0.092	moderately benign-leaning
SaProt	LLR -6.80	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -3.8
Regional constraint	o/e 0.98	unconstrained · MANE · 14 kb · p 0.68 · regional, not allelic
Overall
CADD	0.003	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 0.029% East Asian · 13/44,826 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.000994% 16/1,610,352 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.029%	3,448
European (non-Finnish)	0.000255%	392,579

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: AADAC
Protein: p.Phe376Leu
Coding: c.1126T>C
MANE Select: NM_001086
dbSNP: rs187652875
Type: single nucleotide variant
Location: chr3:151828098 (GRCh38)
Gene constraint: LOEUF 1.126 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.64

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

Similar variants

AADAC p.Ala121Gly Uncertain significance ★ ⚠ same type
AADAC p.Ala16Val Uncertain significance ★ ⚠ same type
AADAC p.Ala319Glu Uncertain significance ★ ⚠ same type
AADAC p.Arg146Ser Uncertain significance ★ ⚠ same type
AADAC p.Arg169Cys Uncertain significance ★ ⚠ same type
AADAC p.Arg169His Uncertain significance ★ ⚠ same type
AADAC p.Arg330Cys Uncertain significance ★ ⚠ same type
AADAC p.Arg92Gly 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/aadac-p-phe376leu (accessed [today's date]).

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