Is CHPF2 p.Arg656Trp (c.1966C>T) pathogenic?

CHPF2 p.Arg656Trp (c.1966C>T) is classified Uncertain significance in CHPF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-29). AlphaMissense: likely benign (0.155); Ultra-rare (popmax 0.0253%, sas).

How common is CHPF2 p.Arg656Trp (c.1966C>T) in the general population?

CHPF2 p.Arg656Trp (c.1966C>T) is ultra-rare (popmax 0.0253%, sas) (gnomAD).

What do computational predictors say about CHPF2 p.Arg656Trp (c.1966C>T)?

AlphaMissense predicts likely benign (score 0.155) — an in-silico prediction, not a clinical call.

CHPF2 p.Arg656Trp

c.1966C>T · rs542748933 · VCV2464892

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.155 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0253%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.155	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -8.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -1, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 4,666 bp · p 0.76 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0253% South Asian · 23/90,854 alleles

Filtering AF 0.0172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0146%

Overall 0.00317% 51/1,609,862 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0253%	3,950
African / African-American	0.016%	6,247
Remaining individualsnot grpmax-eligible	0.00964%	10,379
Admixed American	0.00167%	59,866
European (non-Finnish)	0.000764%	130,893

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: CHPF2
Protein: p.Arg656Trp
Coding: c.1966C>T
MANE Select: NM_019015
dbSNP: rs542748933
Type: single nucleotide variant
Location: chr7:151238328 (GRCh38)
Gene constraint: LOEUF 1.136 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.86
Residue 656: the 'disordered' region

Full CHPF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHPF2 p.Arg656Pro Uncertain significance ★ ⚠ same residue
CHPF2 p.Arg254His Benign ★★ same type
CHPF2 p.Arg460Gln Benign/Likely benign ★★ same type
CHPF2 p.Ala189Ser Uncertain significance ★ ⚠ same type
CHPF2 p.Ala216Thr Uncertain significance ★ ⚠ same type
CHPF2 p.Ala220Thr Uncertain significance ★ ⚠ same type
CHPF2 p.Ala352Gly Uncertain significance ★ ⚠ same type
CHPF2 p.Ala406Val 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/chpf2-p-arg656trp (accessed [today's date]).

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