Is AGA p.Leu7Phe (c.21G>T) pathogenic?

AGA p.Leu7Phe (c.21G>T) is classified Uncertain significance in AGA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-24). AlphaMissense: likely benign (0.0548); Ultra-rare (popmax 0.0274%, sas).

How common is AGA p.Leu7Phe (c.21G>T) in the general population?

AGA p.Leu7Phe (c.21G>T) is ultra-rare (popmax 0.0274%, sas) (gnomAD).

What do computational predictors say about AGA p.Leu7Phe (c.21G>T)?

AlphaMissense predicts likely benign (score 0.0548) — an in-silico prediction, not a clinical call.

AGA p.Leu7Phe

c.21G>T · VCV3362224

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0548 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0274%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0548	likely benign
REVEL	0.254	benign-leaning
SaProt	LLR -7.61	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 -7.6	GERP -0.96
Regional constraint	o/e 1.02	unconstrained · MANE · 11 kb · p 0.64 · regional, not allelic
Overall
CADD	1.468	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 0.0274% South Asian · 25/91,080 alleles

Filtering AF 0.019% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0163%

Overall 0.00161% 26/1,613,976 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0274%	3,643
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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: AGA
Protein: p.Leu7Phe
Coding: c.21G>T
MANE Select: NM_000027
Type: single nucleotide variant
Location: chr4:177442355 (GRCh38)
Gene constraint: LOEUF 0.938 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.41 · 2 PDB

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

Similar variants

AGA p.Leu7= Likely benign ★ same residue
AGA c.127+1G>A Likely pathogenic ★★ same type
AGA c.127+1G>T Likely pathogenic ★★ same type
AGA c.128-2A>G Pathogenic ★★ same type
AGA c.281+1G>T Likely pathogenic ★★ same type
AGA c.395-8A>G Pathogenic/Likely pathogenic ★★ same type
AGA c.508-2A>C Likely pathogenic ★★ same type
AGA c.508-2A>G Likely pathogenic ★★ 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/aga-p-leu7phe (accessed [today's date]).

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