Is CENPI p.Ala674Asp (c.2021C>A) pathogenic?

CENPI p.Ala674Asp (c.2021C>A) is classified Uncertain significance in CENPI (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-27). AlphaMissense: likely benign (0.1213); Very rare (popmax 0.00262%, amr).

How common is CENPI p.Ala674Asp (c.2021C>A) in the general population?

CENPI p.Ala674Asp (c.2021C>A) is very rare (popmax 0.00262%, amr) (gnomAD).

What do computational predictors say about CENPI p.Ala674Asp (c.2021C>A)?

AlphaMissense predicts likely benign (score 0.1213) — an in-silico prediction, not a clinical call.

CENPI p.Ala674Asp

c.2021C>A · VCV3831562

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1213 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00262%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1213	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -6.61	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 0.082	GERP -1.4
Regional constraint	o/e 0.83	unconstrained · MANE · 62 kb · p 9e-05 · regional, not allelic
Overall
CADD	6.006	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 0.00262% Admixed American · 1/38,232 alleles

Filtering AF 9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000424% 5/1,179,798 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00262%	38,232
Remaining individualsnot grpmax-eligible	0.00216%	46,241
European (non-Finnish)	0.000339%	294,914

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: CENPI
Protein: p.Ala674Asp
Coding: c.2021C>A
MANE Select: NM_001386188
Type: single nucleotide variant
Location: chrX:101148088 (GRCh38)
Structure: AlphaFold pLDDT 74.27 · 12 PDB

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

Similar variants

CENPI p.Val10Ile Benign ★★ same type
CENPI p.Val276Met Benign ★★ same type
CENPI c.1195+6A>G Uncertain significance ★ same type
CENPI c.687+8C>T Uncertain significance ★ same type
CENPI p.Ala147Gly Uncertain significance ★ ⚠ same type
CENPI p.Ala479Val Uncertain significance ★ same type
CENPI p.Ala692Thr Uncertain significance ★ ⚠ same type
CENPI p.Arg177Cys 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/cenpi-p-ala674asp (accessed [today's date]).

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