Is RFWD3 p.Arg648= (c.1942C>A) pathogenic?

RFWD3 p.Arg648= (c.1942C>A) is classified Likely benign in RFWD3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-06-30). Very rare (popmax 0.0011%, sas); Associated with RFWD3-related disorder.

What condition is associated with RFWD3 p.Arg648= (c.1942C>A)?

RFWD3 p.Arg648= (c.1942C>A) is associated with RFWD3-related disorder (ClinVar).

How common is RFWD3 p.Arg648= (c.1942C>A) in the general population?

RFWD3 p.Arg648= (c.1942C>A) is very rare (popmax 0.0011%, sas) (gnomAD).

RFWD3 p.Arg648=

c.1942C>A · rs755874703 · VCV3029390

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

RFWD3-related disorder

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 5.5	phastCons 1
Overall
CADD	10.86	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,068 alleles

Overall 0.000124% 2/1,614,086 alleles · very rare exomes 2/1,461,848 · genomes 0/152,238 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,068
European (non-Finnish)	8.47e-05%	1,180,022

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.Arg648=
Coding: c.1942C>A
MANE Select: NM_018124
dbSNP: rs755874703
Type: single nucleotide variant
Location: chr16:74628479 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.95 · 1 PDB
Residue 648: a turn

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

Disease context

RFWD3-related disorder

Similar variants

RFWD3 p.Arg648Gln Uncertain significance ★ ⚠ same residue
RFWD3 p.Arg648Trp Uncertain significance ★ ⚠ same residue
RFWD3 p.Ser408Cys Uncertain significance ★ ⚠ same condition
RFWD3 p.Lys480Ter Uncertain significance same condition
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

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-arg648 (accessed [today's date]).

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