Is RFWD3 p.Arg451= (c.1353G>T) pathogenic?

RFWD3 p.Arg451= (c.1353G>T) is classified Likely benign in RFWD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-08). Very rare (popmax 0.00267%, afr).

How common is RFWD3 p.Arg451= (c.1353G>T) in the general population?

RFWD3 p.Arg451= (c.1353G>T) is very rare (popmax 0.00267%, afr) (gnomAD).

RFWD3 p.Arg451=

c.1353G>T · rs374263739 · VCV1977679

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.2
Overall
CADD	2.07	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,918 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,614,062 alleles · very rare exomes 1/1,461,882 · genomes 2/152,180 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,459
East Asian	0.00223%	44,894

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: RFWD3
Protein: p.Arg451=
Coding: c.1353G>T
MANE Select: NM_018124
dbSNP: rs374263739
Type: single nucleotide variant
Location: chr16:74636419 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.95 · 1 PDB

Full RFWD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RFWD3 p.Arg451Trp Uncertain significance ★★ ⚠ same residue
RFWD3 p.Arg451Gln Uncertain significance ★ ⚠ same residue
RFWD3 p.Arg451Leu Uncertain significance ★ ⚠ same residue
RFWD3 p.Ala22Pro Uncertain significance ★★ ⚠ same type
RFWD3 p.Ala231Pro Uncertain significance ★★ ⚠ same type
RFWD3 p.Ala244Val Uncertain significance ★★ ⚠ same type
RFWD3 p.Ala24Val Uncertain significance ★★ ⚠ same type
RFWD3 p.Ala372Thr 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/rfwd3-p-arg451 (accessed [today's date]).

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