Is CPSF7 p.Arg78His (c.233G>A) pathogenic?

CPSF7 p.Arg78His (c.233G>A) is classified Uncertain significance in CPSF7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-24). AlphaMissense: ambiguous (0.3874); Very rare (popmax 0.00223%, eas).

How common is CPSF7 p.Arg78His (c.233G>A) in the general population?

CPSF7 p.Arg78His (c.233G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CPSF7 p.Arg78His (c.233G>A)?

AlphaMissense predicts ambiguous (score 0.3874) — an in-silico prediction, not a clinical call.

CPSF7 p.Arg78His

c.233G>A · VCV4656263

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3874 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3874	ambiguous
REVEL	0.203	benign-leaning
SaProt	LLR -6.52	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 18 kb · p 2.7e-11 · regional, not allelic
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

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 · 1/44,898 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000558% 9/1,614,036 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,898
Remaining individualsnot grpmax-eligible	0.0016%	62,488
South Asian	0.0011%	91,086
European (non-Finnish)	0.000508%	196,671

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: CPSF7
Protein: p.Arg78His
Coding: c.233G>A
MANE Select: NM_001142565
Type: single nucleotide variant
Location: chr11:61421430 (GRCh38)
Gene constraint: LOEUF 0.13 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.55 · 1 PDB

Full CPSF7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPSF7 p.Arg78Cys Uncertain significance ★ ⚠ same residue
CPSF7 c.-15C>T Uncertain significance ★ same type
CPSF7 c.-21C>G Uncertain significance ★ same type
CPSF7 c.-56+117C>T Uncertain significance ★ same type
CPSF7 c.-56+123C>G Uncertain significance ★ same type
CPSF7 c.-56+124C>T Uncertain significance ★ same type
CPSF7 c.-56+133G>C Uncertain significance ★ same type
CPSF7 c.-56+138G>C 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/cpsf7-p-arg78his (accessed [today's date]).

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