Is CPSF6 p.Asp54Ala (c.161A>C) pathogenic?

CPSF6 p.Asp54Ala (c.161A>C) is classified Uncertain significance in CPSF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-08). AlphaMissense: likely pathogenic (0.8099); Very rare (popmax 0.0022%, nfe).

How common is CPSF6 p.Asp54Ala (c.161A>C) in the general population?

CPSF6 p.Asp54Ala (c.161A>C) is very rare (popmax 0.0022%, nfe) (gnomAD).

What do computational predictors say about CPSF6 p.Asp54Ala (c.161A>C)?

AlphaMissense predicts likely pathogenic (score 0.8099) — an in-silico prediction, not a clinical call.

CPSF6 p.Asp54Ala

c.161A>C · VCV4006398

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8099 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8099	likely pathogenic
REVEL	0.252	benign-leaning
SaProt	LLR -7.70	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 18 kb · p 5.3e-10 · regional, not allelic
Overall
CADD	24.0	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 0.0022% European (non-Finnish) · 26/1,179,870 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00161% 26/1,613,094 alleles · very rare

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.Asp54Ala
Coding: c.161A>C
MANE Select: NM_007007
Type: single nucleotide variant
Location: chr12:69251229 (GRCh38)
Gene constraint: LOEUF 0.306 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.11 · 17 PDB
Residue 54: the 'necessary for interaction with nxf1' region

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-asp54ala (accessed [today's date]).

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