Is RFWD3 p.Pro656= (c.1968T>C) pathogenic?

RFWD3 p.Pro656= (c.1968T>C) is classified Uncertain significance in RFWD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-20). Very rare (popmax 0.00445%, eas); Associated with Fanconi anemia, complementation group W.

What condition is associated with RFWD3 p.Pro656= (c.1968T>C)?

RFWD3 p.Pro656= (c.1968T>C) is associated with Fanconi anemia, complementation group W (ClinVar).

How common is RFWD3 p.Pro656= (c.1968T>C) in the general population?

RFWD3 p.Pro656= (c.1968T>C) is very rare (popmax 0.00445%, eas) (gnomAD).

RFWD3 p.Pro656=

c.1968T>C · rs1294963127 · VCV2807145

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Conditions

Fanconi anemia, complementation group W

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 0.39	phastCons 0.72
Overall
CADD	7.519	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00445% East Asian · 2/44,894 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000186% 3/1,613,752 alleles · very rare exomes 2/1,461,640 · genomes 1/152,112 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,447
African / African-American	0.00134%	74,898

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.Pro656=
Coding: c.1968T>C
MANE Select: NM_018124
dbSNP: rs1294963127
Type: single nucleotide variant
Location: chr16:74628453 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.95 · 1 PDB
Residue 656: a β-strand

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

Disease context

Fanconi anemia, complementation group W — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RFWD3 p.Ala732Gly Uncertain significance ★★ ⚠ same condition
RFWD3 p.Cys548Tyr Uncertain significance ★★ ⚠ same condition
RFWD3 p.Gln577His Uncertain significance ★★ ⚠ same condition
RFWD3 p.Pro148Leu Uncertain significance ★★ ⚠ same condition
RFWD3 p.Ser526Asn Uncertain significance ★★ same condition
RFWD3 p.Val397Leu Uncertain significance ★★ ⚠ same condition
RFWD3 c.1755-33G>A Benign ★★ same condition
RFWD3 p.Met767Val Likely benign ★★ same condition

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-pro656 (accessed [today's date]).

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