Is RFWD3 p.Pro680= (c.2040A>G) pathogenic?

RFWD3 p.Pro680= (c.2040A>G) is classified Benign in RFWD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-01). Ultra-rare (popmax 0.0419%, nfe).

How common is RFWD3 p.Pro680= (c.2040A>G) in the general population?

RFWD3 p.Pro680= (c.2040A>G) is ultra-rare (popmax 0.0419%, nfe) (gnomAD).

RFWD3 p.Pro680=

c.2040A>G · rs143173893 · VCV2055111

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0419%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.1
Overall
CADD	0.394	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0419% European (non-Finnish) · 494/1,180,016 alleles

Filtering AF 0.0388% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0376%

Overall 0.0622% 1,004/1,614,180 alleles · ultra-rare exomes 899/1,461,878 · genomes 105/152,302 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.35%	74
Remaining individualsnot grpmax-eligible	0.104%	962
European (non-Finnish)grpmax	0.0419%	2,389
Middle Eastern	0.033%	3,031
Finnishnot grpmax-eligible	0.0328%	3,050
Admixed American	0.0183%	5,457
African / African-American	0.0107%	9,380
South Asian	0.0022%	45,540

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro680=
Coding: c.2040A>G
MANE Select: NM_018124
dbSNP: rs143173893
Type: single nucleotide variant
Location: chr16:74626484 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.95 · 1 PDB
Residue 680: a β-strand

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

Similar variants

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
RFWD3 p.Ala447Gly Uncertain significance ★★ ⚠ same type
RFWD3 p.Ala581Gly Uncertain significance ★★ ⚠ same type
RFWD3 p.Ala5Thr 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-pro680 (accessed [today's date]).

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