Is CPSF6 p.Val101Ile (c.301G>A) pathogenic?

CPSF6 p.Val101Ile (c.301G>A) is classified Uncertain significance in CPSF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-17). AlphaMissense: likely benign (0.075); Ultra-rare (popmax 0.0829%, mid).

How common is CPSF6 p.Val101Ile (c.301G>A) in the general population?

CPSF6 p.Val101Ile (c.301G>A) is ultra-rare (popmax 0.0829%, mid) (gnomAD).

What do computational predictors say about CPSF6 p.Val101Ile (c.301G>A)?

AlphaMissense predicts likely benign (score 0.075) — an in-silico prediction, not a clinical call.

CPSF6 p.Val101Ile

c.301G>A · rs150030798 · VCV2277437

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.075 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0829%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.075	likely benign
REVEL	0.172	moderately benign-leaning
SaProt	LLR -5.69	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 12	GERP 2, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 18 kb · p 5.3e-10 · regional, not allelic
Overall
CADD	21.5	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 0.0829% Middle Eastern · 5/6,028 alleles

Filtering AF 0.0327% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0211%

Overall 0.00371% 59/1,590,446 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0829%	1,206
South Asian	0.0116%	8,651
European (non-Finnish)	0.00359%	27,823
Remaining individualsnot grpmax-eligible	0.00163%	61,340
African / African-American	0.00136%	73,706

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: CPSF6
Protein: p.Val101Ile
Coding: c.301G>A
MANE Select: NM_007007
dbSNP: rs150030798
Type: single nucleotide variant
Location: chr12:69253081 (GRCh38)
Gene constraint: LOEUF 0.306 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.11 · 17 PDB
Residue 101: the rrm domain; the 'necessary for interaction with nxf1' region; the 'necessary for interaction with nudt21/cpsf5' region; the 'necessary for nuclear paraspeckles localization' region; an α-helix

Full CPSF6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPSF6 p.Arg118Trp Uncertain significance ★ ⚠ same type
CPSF6 p.Arg206His Uncertain significance ★ ⚠ same type
CPSF6 p.Arg272Cys Uncertain significance ★ ⚠ same type
CPSF6 p.Arg326His Uncertain significance ★ ⚠ same type
CPSF6 p.Arg542His Uncertain significance ★ ⚠ same type
CPSF6 p.Arg546Cys Uncertain significance ★ ⚠ same type
CPSF6 p.Asn19Ser Uncertain significance ★ ⚠ same type
CPSF6 p.Asp518Glu 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/cpsf6-p-val101ile (accessed [today's date]).

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