Is NCAPH p.Arg451Cys (c.1351C>T) pathogenic?

NCAPH p.Arg451Cys (c.1351C>T) is classified Uncertain significance in NCAPH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-10-04). AlphaMissense: likely benign (0.0716); Ultra-rare (popmax 0.015%, amr).

How common is NCAPH p.Arg451Cys (c.1351C>T) in the general population?

NCAPH p.Arg451Cys (c.1351C>T) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about NCAPH p.Arg451Cys (c.1351C>T)?

AlphaMissense predicts likely benign (score 0.0716) — an in-silico prediction, not a clinical call.

NCAPH p.Arg451Cys

c.1351C>T · rs755156857 · VCV2342705

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0716 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0716	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -8.72	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 0.59	GERP 0.86
Regional constraint	o/e 0.86	unconstrained · MANE · 38 kb · p 2.5e-05 · regional, not allelic
Overall
CADD	25.0	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 0.015% Admixed American · 9/59,950 alleles

Filtering AF 0.00774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00409% 66/1,613,708 alleles · ultra-rare exomes 55/1,461,608 · genomes 11/152,100 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,661
Remaining individualsnot grpmax-eligible	0.0144%	6,942
African / African-American	0.00401%	24,959
European (non-Finnish)	0.00356%	28,093
Finnishnot grpmax-eligible	0.00312%	32,002
South Asian	0.0011%	91,040

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.Arg451Cys
Coding: c.1351C>T
MANE Select: NM_015341
dbSNP: rs755156857
Type: single nucleotide variant
Location: chr2:96359187 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 60.16 · 1 PDB
Residue 451: the 'disordered' region

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

Similar variants

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
NCAPH p.Ala198Pro Uncertain significance ★ ⚠ same type
NCAPH p.Ala304Val 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/ncaph-p-arg451cys (accessed [today's date]).

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