Is CENPF p.Leu322Pro (c.965T>C) pathogenic?

CENPF p.Leu322Pro (c.965T>C) is classified Uncertain significance in CENPF (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-13). AlphaMissense: likely pathogenic (0.8691); Rare (popmax 0.123%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CENPF p.Leu322Pro (c.965T>C)?

CENPF p.Leu322Pro (c.965T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CENPF p.Leu322Pro (c.965T>C) in the general population?

CENPF p.Leu322Pro (c.965T>C) is rare (popmax 0.123%, nfe) (gnomAD).

What do computational predictors say about CENPF p.Leu322Pro (c.965T>C)?

AlphaMissense predicts likely pathogenic (score 0.8691) — an in-silico prediction, not a clinical call.

CENPF p.Leu322Pro

c.965T>C · rs140399039 · VCV2063702

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8691 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.123%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8691	likely pathogenic · top 1% in CENPF
REVEL	0.621	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 50 kb · p 0.16 · regional, not allelic
Overall
CADD	25.3	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 0.123% European (non-Finnish) · 1,446/1,179,968 alleles

Filtering AF 0.117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.115%

Overall 0.0952% 1,537/1,613,880 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.123%	816
Remaining individualsnot grpmax-eligible	0.0736%	1,358
Admixed American	0.0417%	2,399
Middle Eastern	0.0164%	6,082
African / African-American	0.0134%	7,490
Finnishnot grpmax-eligible	0.0125%	8,004
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,594

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: CENPF
Protein: p.Leu322Pro
Coding: c.965T>C
MANE Select: NM_016343
dbSNP: rs140399039
Type: single nucleotide variant
Location: chr1:214622178 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI <0.01 (gnomAD)
Residue 322: the 'interaction with snap25 and required for localization to the cytoplasm' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CENPF p.Ala1268Val Uncertain significance ★★ ⚠ same condition
CENPF p.Ala1626Val Uncertain significance ★★ ⚠ same condition
CENPF p.Ala1714Thr Uncertain significance ★★ ⚠ same condition
CENPF p.Ala212Asp Uncertain significance ★★ same condition
CENPF p.Ala2616Val Uncertain significance ★★ ⚠ same condition
CENPF p.Arg1325Lys Uncertain significance ★★ ⚠ same condition
CENPF p.Arg1653Trp Uncertain significance ★★ ⚠ same condition
CENPF p.Arg178Gln Uncertain significance ★★ ⚠ same condition

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/cenpf-p-leu322pro (accessed [today's date]).

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