Is CHPF2 p.Arg421His (c.1262G>A) pathogenic?

CHPF2 p.Arg421His (c.1262G>A) is classified Uncertain significance in CHPF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-12). AlphaMissense: likely benign (0.0992); Very rare (popmax 0.00223%, eas).

How common is CHPF2 p.Arg421His (c.1262G>A) in the general population?

CHPF2 p.Arg421His (c.1262G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CHPF2 p.Arg421His (c.1262G>A)?

AlphaMissense predicts likely benign (score 0.0992) — an in-silico prediction, not a clinical call.

CHPF2 p.Arg421His

c.1262G>A · rs746382000 · VCV3144520

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0992 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0992	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -6.83	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 4.4	GERP -0.58, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 4,666 bp · p 0.76 · regional, not allelic
Overall
CADD	23.3	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 0.00223% East Asian · 1/44,892 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00151% 22/1,460,820 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,892
Admixed American	0.00167%	60,034
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.00153%	65,551
South Asian	0.0011%	91,088

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.Arg421His
Coding: c.1262G>A
MANE Select: NM_019015
dbSNP: rs746382000
Type: single nucleotide variant
Location: chr7:151237624 (GRCh38)
Gene constraint: LOEUF 1.136 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.86

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

Similar variants

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
CHPF2 p.Ala547Pro 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-arg421his (accessed [today's date]).

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