Is RNASE3 p.Val154Phe (c.460G>T) pathogenic?

RNASE3 p.Val154Phe (c.460G>T) is classified Uncertain significance in RNASE3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-07). AlphaMissense: ambiguous (0.5635); Ultra-rare (popmax 0.0163%, afr).

How common is RNASE3 p.Val154Phe (c.460G>T) in the general population?

RNASE3 p.Val154Phe (c.460G>T) is ultra-rare (popmax 0.0163%, afr) (gnomAD).

What do computational predictors say about RNASE3 p.Val154Phe (c.460G>T)?

AlphaMissense predicts ambiguous (score 0.5635) — an in-silico prediction, not a clinical call.

RNASE3 p.Val154Phe

c.460G>T · VCV3314635

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5635 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0163%, afr)

Computational evidence

Protein change
AlphaMissense	0.5635	ambiguous
REVEL	0.524	indeterminate
SaProt	LLR -12.67	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 0.71, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 479 bp · p 0.35 · regional, not allelic
Overall
CADD	19.95	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 0.0163% African / African-American · 12/73,572 alleles

Filtering AF 0.00937% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00734%

Overall 0.000745% 12/1,611,562 alleles · ultra-rare exomes 6/1,460,566 · genomes 6/150,996 · joint denominator

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: RNASE3
Protein: p.Val154Phe
Coding: c.460G>T
MANE Select: NM_002935
Type: single nucleotide variant
Location: chr14:20892146 (GRCh38)
Gene constraint: LOEUF 1.939 · pLI 0.11 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 90.69 · 11 PDB
Residue 154: a β-strand

Full RNASE3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RAF1 p.Ile154Met Conflicting classifications of pathogenicity ★ ⚠ same residue
RAF1 p.Ile154Val Uncertain significance ★ ⚠ same residue
RNASE3 p.Val154Leu Uncertain significance ★ ⚠ same residue
RAF1 p.Arg256Ser Likely pathogenic ★★★ ⚠ same type
RAF1 p.Gly361Ala Pathogenic ★★★ ⚠ same type
RAF1 p.Leu613Val Pathogenic ★★★ same type
RAF1 p.Pro261Ser Pathogenic ★★★ ⚠ same type
RAF1 p.Ser257Leu 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/rnase3-p-val154phe (accessed [today's date]).

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