Is NCAPH p.Pro35Leu (c.104C>T) pathogenic?

NCAPH p.Pro35Leu (c.104C>T) is classified Uncertain significance in NCAPH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-23). AlphaMissense: likely benign (0.0824); Ultra-rare (popmax 0.0267%, eas).

How common is NCAPH p.Pro35Leu (c.104C>T) in the general population?

NCAPH p.Pro35Leu (c.104C>T) is ultra-rare (popmax 0.0267%, eas) (gnomAD).

What do computational predictors say about NCAPH p.Pro35Leu (c.104C>T)?

AlphaMissense predicts likely benign (score 0.0824) — an in-silico prediction, not a clinical call.

NCAPH p.Pro35Leu

c.104C>T · rs574607366 · VCV2570389

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0824 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0824	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -6.72	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 2.6	GERP 1.6, phastCons 0.045
Regional constraint	o/e 0.86	unconstrained · MANE · 38 kb · p 2.5e-05 · regional, not allelic
Overall
CADD	17.18	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 0.0267% East Asian · 12/44,888 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00186% 30/1,614,216 alleles · ultra-rare exomes 24/1,461,886 · genomes 6/152,330 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0267%	3,741
Admixed American	0.005%	20,007
South Asian	0.00439%	22,772
Remaining individualsnot grpmax-eligible	0.0016%	62,512
African / African-American	0.00133%	75,050
European (non-Finnish)	0.000763%	131,116

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.Pro35Leu
Coding: c.104C>T
MANE Select: NM_015341
dbSNP: rs574607366
Type: single nucleotide variant
Location: chr2:96341726 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 60.16 · 1 PDB
Residue 35: the 'disordered' region

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

Similar variants

NCAPH p.Pro35Arg Uncertain significance ★ ⚠ 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-pro35leu (accessed [today's date]).

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