Is ARGFX p.Phe228Leu (c.684C>G) pathogenic?

ARGFX p.Phe228Leu (c.684C>G) is classified Uncertain significance in ARGFX (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-30). AlphaMissense: likely benign (0.3159); Very rare (popmax 0.00549%, sas).

How common is ARGFX p.Phe228Leu (c.684C>G) in the general population?

ARGFX p.Phe228Leu (c.684C>G) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about ARGFX p.Phe228Leu (c.684C>G)?

AlphaMissense predicts likely benign (score 0.3159) — an in-silico prediction, not a clinical call.

ARGFX p.Phe228Leu

c.684C>G · rs1254772349 · VCV2330121

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3159 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3159	likely benign
REVEL	0.157	moderately benign-leaning
SaProt	LLR -4.37	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 -0.55	GERP -0.26
Regional constraint	o/e 0.87	unconstrained · MANE · 16 kb · p 0.019 · regional, not allelic
Overall
CADD	3.159	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 0.00549% South Asian · 5/91,078 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000342% 5/1,461,880 alleles · very rare

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: ARGFX
Protein: p.Phe228Leu
Coding: c.684C>G
MANE Select: NM_001012659
dbSNP: rs1254772349
Type: single nucleotide variant
Location: chr3:121586336 (GRCh38)
Gene constraint: LOEUF 1.843 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.78

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

Similar variants

ARGFX p.Ala190Glu Uncertain significance ★ ⚠ same type
ARGFX p.Arg114Thr Uncertain significance ★ ⚠ same type
ARGFX p.Arg129Gln Uncertain significance ★ ⚠ same type
ARGFX p.Arg129Trp Uncertain significance ★ ⚠ same type
ARGFX p.Arg130Gln Uncertain significance ★ ⚠ same type
ARGFX p.Arg212Met Uncertain significance ★ ⚠ same type
ARGFX p.Arg82His Uncertain significance ★ ⚠ same type
ARGFX p.Asn188Ile 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/argfx-p-phe228leu (accessed [today's date]).

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