Is ARSF p.Pro475Leu (c.1424C>T) pathogenic?

ARSF p.Pro475Leu (c.1424C>T) is classified Uncertain significance in ARSF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-22). AlphaMissense: likely pathogenic (0.6876); Ultra-rare (popmax 0.0618%, afr).

How common is ARSF p.Pro475Leu (c.1424C>T) in the general population?

ARSF p.Pro475Leu (c.1424C>T) is ultra-rare (popmax 0.0618%, afr) (gnomAD).

What do computational predictors say about ARSF p.Pro475Leu (c.1424C>T)?

AlphaMissense predicts likely pathogenic (score 0.6876) — an in-silico prediction, not a clinical call.

ARSF p.Pro475Leu

c.1424C>T · VCV4149477

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6876 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0618%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6876	likely pathogenic
REVEL	0.47	indeterminate
SaProt	LLR -15.25	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 1.5, phastCons 0.98
Regional constraint	o/e 1.04	unconstrained · MANE · 44 kb · p 0.34 · regional, not allelic
Overall
CADD	18.89	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0618% African / African-American · 35/56,658 alleles

Filtering AF 0.0456% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0401%

Overall 0.00621% 75/1,207,014 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0618%	1,619
Middle Eastern	0.0229%	4,365
South Asian	0.00888%	11,262
Remaining individualsnot grpmax-eligible	0.00631%	15,839
Admixed American	0.0044%	22,713
European (non-Finnish)	0.00313%	31,933
Finnishnot grpmax-eligible	0.00216%	46,335

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: ARSF
Protein: p.Pro475Leu
Coding: c.1424C>T
MANE Select: NM_001201539
Type: single nucleotide variant
Location: chrX:3112207 (GRCh38)
Structure: AlphaFold pLDDT 90.98

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

Similar variants

ARSF c.1102+5G>A Likely benign ★★ same type
ARSF p.Pro6= Benign ★★ same type
ARSF p.Ala112Ser Uncertain significance ★ ⚠ same type
ARSF p.Ala411Pro Uncertain significance ★ ⚠ same type
ARSF p.Ala411Thr Uncertain significance ★ ⚠ same type
ARSF p.Ala84Pro Uncertain significance ★ ⚠ same type
ARSF p.Arg103Cys Uncertain significance ★ ⚠ same type
ARSF p.Arg179His 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/arsf-p-pro475leu (accessed [today's date]).

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