Is NCAPH p.Pro243Ser (c.727C>T) pathogenic?

NCAPH p.Pro243Ser (c.727C>T) is classified Uncertain significance in NCAPH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-25). AlphaMissense: ambiguous (0.4418); Ultra-rare (popmax 0.0328%, nfe).

How common is NCAPH p.Pro243Ser (c.727C>T) in the general population?

NCAPH p.Pro243Ser (c.727C>T) is ultra-rare (popmax 0.0328%, nfe) (gnomAD).

What do computational predictors say about NCAPH p.Pro243Ser (c.727C>T)?

AlphaMissense predicts ambiguous (score 0.4418) — an in-silico prediction, not a clinical call.

NCAPH p.Pro243Ser

c.727C>T · rs199755752 · VCV2455969

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4418 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0328%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4418	ambiguous
REVEL	0.705	pathogenic-leaning
SaProt	LLR -10.58	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 38 kb · p 2.5e-05 · regional, not allelic
Overall
CADD	26.0	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 0.0328% European (non-Finnish) · 385/1,173,430 alleles

Filtering AF 0.0301% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.029%

Overall 0.0249% 398/1,597,736 alleles · ultra-rare exomes 386/1,445,598 · genomes 12/152,138 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0328%	3,048
Remaining individualsnot grpmax-eligible	0.0097%	10,306
African / African-American	0.00539%	18,554
Admixed American	0.00533%	18,749

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: NCAPH
Protein: p.Pro243Ser
Coding: c.727C>T
MANE Select: NM_015341
dbSNP: rs199755752
Type: single nucleotide variant
Location: chr2:96351837 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 60.16 · 1 PDB
Residue 243: a UniProt-annotated variant site (in mcph23; impairs mitotic chromosome compaction)

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

Similar variants

NCAPH p.Pro243Leu Pathogenic ⚠ same residue
NCAPH p.Arg451Cys Uncertain significance ★★ ⚠ same type
NCAPH c.1002+9A>G Benign/Likely benign ★★ same type
NCAPH p.Arg221Gly Benign ★★ same type
NCAPH p.Asp377= Benign ★★ same type
NCAPH p.Val384Ile Benign/Likely benign ★★ same type
NCAPH p.Val539Ala Benign ★★ same type
NCAPH c.19+1G>C Likely pathogenic ★ 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/ncaph-p-pro243ser (accessed [today's date]).

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