Is AGA p.Phe75Cys (c.224T>G) pathogenic?

AGA p.Phe75Cys (c.224T>G) is classified Uncertain significance in AGA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: ambiguous (0.4791); Very rare (popmax 0.0039%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AGA p.Phe75Cys (c.224T>G)?

AGA p.Phe75Cys (c.224T>G) is associated with Inborn genetic diseases (ClinVar).

How common is AGA p.Phe75Cys (c.224T>G) in the general population?

AGA p.Phe75Cys (c.224T>G) is very rare (popmax 0.0039%, nfe) (gnomAD).

What do computational predictors say about AGA p.Phe75Cys (c.224T>G)?

AlphaMissense predicts ambiguous (score 0.4791) — an in-silico prediction, not a clinical call.

AGA p.Phe75Cys

c.224T>G · VCV4248945

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4791 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0039%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4791	ambiguous
REVEL	0.653	pathogenic-leaning
SaProt	LLR -11.24	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 11 kb · p 0.64 · regional, not allelic
Overall
CADD	25.1	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 0.0039% European (non-Finnish) · 46/1,180,042 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00267%

Overall 0.00328% 48/1,461,884 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0039%	25,653
Remaining individualsnot grpmax-eligible	0.0032%	31,256

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.Phe75Cys
Coding: c.224T>G
MANE Select: NM_000027
Type: single nucleotide variant
Location: chr4:177440330 (GRCh38)
Gene constraint: LOEUF 0.938 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.41 · 2 PDB
Residue 75: a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AGA p.Phe75Ser Uncertain significance same residue
AGA p.Ala285Gly Uncertain significance ★★ ⚠ same condition
AGA p.Asn143Ser Uncertain significance ★★ ⚠ same condition
AGA p.Ala101= Benign/Likely benign ★★ same condition
AGA p.Phe326= Likely benign ★★ same condition
AGA p.Val57= Likely benign ★★ same condition
AGA c.394+1G>A Likely pathogenic ★ same condition
AGA p.Asp261Asn Uncertain significance ★ ⚠ same condition

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-phe75cys (accessed [today's date]).

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