Is ARC p.Leu333Phe (c.997C>T) pathogenic?

ARC p.Leu333Phe (c.997C>T) is classified Uncertain significance in ARC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely benign (0.1285); Ultra-rare (popmax 0.0117%, amr).

How common is ARC p.Leu333Phe (c.997C>T) in the general population?

ARC p.Leu333Phe (c.997C>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about ARC p.Leu333Phe (c.997C>T)?

AlphaMissense predicts likely benign (score 0.1285) — an in-silico prediction, not a clinical call.

ARC p.Leu333Phe

c.997C>T · VCV4130570

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1285 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1285	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -6.36	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 3.9	GERP -0.68, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 449 bp · p 2.8e-08 · regional, not allelic
Overall
CADD	19.22	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 0.0117% Admixed American · 7/60,016 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.00093% 15/1,613,540 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,574
Remaining individualsnot grpmax-eligible	0.0032%	31,239
African / African-American	0.00133%	74,934
European (non-Finnish)	0.000424%	235,998

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: ARC
Protein: p.Leu333Phe
Coding: c.997C>T
MANE Select: NM_015193
Type: single nucleotide variant
Location: chr8:142613275 (GRCh38)
Gene constraint: LOEUF 1.393 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.72 · 11 PDB
Residue 333: an α-helix

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

Similar variants

ARC c.*258C>T Benign ★★ same type
ARC p.Ala144Ser Uncertain significance ★ ⚠ same type
ARC p.Arg107Cys Uncertain significance ★ ⚠ same type
ARC p.Arg129His Uncertain significance ★ ⚠ same type
ARC p.Arg304His Uncertain significance ★ ⚠ same type
ARC p.Arg335Cys Uncertain significance ★ ⚠ same type
ARC p.Arg392Gln Uncertain significance ★ ⚠ same type
ARC p.Asp307Glu 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/arc-p-leu333phe (accessed [today's date]).

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