Is CPSF3 p.His608Asp (c.1822C>G) pathogenic?

CPSF3 p.His608Asp (c.1822C>G) is classified Uncertain significance in CPSF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely benign (0.0605); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures.

How common is CPSF3 p.His608Asp (c.1822C>G) in the general population?

CPSF3 p.His608Asp (c.1822C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CPSF3 p.His608Asp (c.1822C>G)?

AlphaMissense predicts likely benign (score 0.0605) — an in-silico prediction, not a clinical call.

CPSF3 p.His608Asp

Q: What condition is associated with CPSF3 p.His608Asp (c.1822C>G)?

CPSF3 p.His608Asp (c.1822C>G) is associated with neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures (ClinVar).

c.1822C>G · VCV4278243

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0605 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures

Computational evidence

Protein change
AlphaMissense	0.0605	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -3.21	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 3.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 20 kb · p 0.011 · regional, not allelic
Overall
CADD	20.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CPSF3
Protein: p.His608Asp
Coding: c.1822C>G
MANE Select: NM_016207
Type: single nucleotide variant
Location: chr2:9467742 (GRCh38)
Gene constraint: LOEUF 1.01 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.41 · 10 PDB

Full CPSF3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CPSF3 p.Ile354Met Uncertain significance ★★ ⚠ same condition
CPSF3 c.51-2165C>G Uncertain significance ★ same condition
CPSF3 p.Ile29Thr Uncertain significance ★ ⚠ same condition
CPSF3 p.Arg218Gln Uncertain significance ⚠ same condition
CPSF3 p.Ala147Val Uncertain significance ★ ⚠ same type
CPSF3 p.Ala190Val Uncertain significance ★ ⚠ same type
CPSF3 p.Ala430Thr Uncertain significance ★ ⚠ same type
CPSF3 p.Ala516Val 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/cpsf3-p-his608asp (accessed [today's date]).

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