Is CPSF6 p.Glu541Asp (c.1623G>C) pathogenic?

CPSF6 p.Glu541Asp (c.1623G>C) is classified Uncertain significance in CPSF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-08). AlphaMissense: likely benign (0.0977); Very rare (popmax 0.00439%, sas).

How common is CPSF6 p.Glu541Asp (c.1623G>C) in the general population?

CPSF6 p.Glu541Asp (c.1623G>C) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about CPSF6 p.Glu541Asp (c.1623G>C)?

AlphaMissense predicts likely benign (score 0.0977) — an in-silico prediction, not a clinical call.

CPSF6 p.Glu541Asp

c.1623G>C · rs751188299 · VCV2340736

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0977	likely benign
REVEL	0.214	benign-leaning
SaProt	LLR -4.89	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 -0.15	GERP -3.9, phastCons 0.028
Regional constraint	o/e 0.42	unconstrained · MANE · 3,097 bp · p 5.8e-16 · regional, not allelic
Overall
CADD	10.99	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 0.00439% South Asian · 4/91,044 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000868% 14/1,613,130 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,761
African / African-American	0.00401%	24,939
Remaining individualsnot grpmax-eligible	0.0016%	62,450
European (non-Finnish)	0.000509%	196,566

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.Glu541Asp
Coding: c.1623G>C
MANE Select: NM_007007
dbSNP: rs751188299
Type: single nucleotide variant
Location: chr12:69262526 (GRCh38)
Gene constraint: LOEUF 0.306 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.11 · 17 PDB
Residue 541: the 'necessary for interaction with srsf3, srsf7 and tra2b/sfrs10' region; the 'arg/ser-rich domain' region; the 'sufficient for nuclear targeting' region; the '(microbial infection) binds to hiv-1 capsid protein p24 (ca)' region; the 'sufficient for nuclear speckle localization' region; the 'necessary for rna-binding' region; the 'disordered' 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-glu541asp (accessed [today's date]).

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