Is NCAPH p.Ser89Thr (c.265T>A) pathogenic?

NCAPH p.Ser89Thr (c.265T>A) is classified Uncertain significance in NCAPH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely benign (0.0656); Ultra-rare (popmax 0.055%, amr).

How common is NCAPH p.Ser89Thr (c.265T>A) in the general population?

NCAPH p.Ser89Thr (c.265T>A) is ultra-rare (popmax 0.055%, amr) (gnomAD).

What do computational predictors say about NCAPH p.Ser89Thr (c.265T>A)?

AlphaMissense predicts likely benign (score 0.0656) — an in-silico prediction, not a clinical call.

NCAPH p.Ser89Thr

c.265T>A · VCV4830139

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0656 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.055%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0656	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -7.81	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 0.58	GERP 0.52, phastCons 0.027
Regional constraint	o/e 0.86	unconstrained · MANE · 38 kb · p 2.5e-05 · regional, not allelic
Overall
CADD	10.42	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 0.055% Admixed American · 33/59,972 alleles

Filtering AF 0.0402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0351%

Overall 0.00205% 33/1,608,910 alleles · ultra-rare exomes 8/1,456,760 · genomes 25/152,150 · 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.Ser89Thr
Coding: c.265T>A
MANE Select: NM_015341
Type: single nucleotide variant
Location: chr2:96341887 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 60.16 · 1 PDB
Residue 89: a modified residue (phosphoserine)

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-ser89thr (accessed [today's date]).

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