Is NCAPH p.Pro596Ser (c.1786C>T) pathogenic?

NCAPH p.Pro596Ser (c.1786C>T) is classified Uncertain significance in NCAPH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-06). AlphaMissense: likely benign (0.0654); Very rare (popmax 8.47e-05%, nfe).

How common is NCAPH p.Pro596Ser (c.1786C>T) in the general population?

NCAPH p.Pro596Ser (c.1786C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about NCAPH p.Pro596Ser (c.1786C>T)?

AlphaMissense predicts likely benign (score 0.0654) — an in-silico prediction, not a clinical call.

NCAPH p.Pro596Ser

c.1786C>T · VCV3917787

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0654 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0654	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -5.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.91 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.11	GERP -2.9
Regional constraint	o/e 0.86	unconstrained · MANE · 38 kb · p 2.5e-05 · regional, not allelic
Overall
CADD	7.929	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 8.47e-05% European (non-Finnish) · 1/1,180,036 alleles

Overall 6.2e-05% 1/1,614,050 alleles · very rare exomes 0/1,461,886 · genomes 1/152,164 · joint denominator

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.Pro596Ser
Coding: c.1786C>T
MANE Select: NM_015341
Type: single nucleotide variant
Location: chr2:96365963 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 60.16 · 1 PDB

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

Similar variants

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
NCAPH p.Ala198Pro 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-pro596ser (accessed [today's date]).

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