Is APH1B p.Phe40Ser (c.119T>C) pathogenic?

APH1B p.Phe40Ser (c.119T>C) is classified Uncertain significance in APH1B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-06). AlphaMissense: likely pathogenic (0.798); Absent from gnomAD v4.1.

How common is APH1B p.Phe40Ser (c.119T>C) in the general population?

APH1B p.Phe40Ser (c.119T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APH1B p.Phe40Ser (c.119T>C)?

AlphaMissense predicts likely pathogenic (score 0.798) — an in-silico prediction, not a clinical call.

APH1B p.Phe40Ser

c.119T>C · VCV3306537

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.798 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.798	likely pathogenic
REVEL	0.788	moderately pathogenic-leaning
SaProt	LLR -13.20	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 28 kb · p 0.63 · regional, not allelic
Overall
CADD	29.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: APH1B
Protein: p.Phe40Ser
Coding: c.119T>C
MANE Select: NM_031301
Type: single nucleotide variant
Location: chr15:63279166 (GRCh38)
Gene constraint: LOEUF 1.327 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.51 · 2 PDB
Residue 40: an α-helix

Full APH1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APH1B p.Ala4Thr Uncertain significance ★ ⚠ same type
APH1B p.Ala76Gly Uncertain significance ★ ⚠ same type
APH1B p.Asn253Ile Uncertain significance ★ ⚠ same type
APH1B p.Asp179Tyr Uncertain significance ★ ⚠ same type
APH1B p.Gly15Arg Uncertain significance ★ ⚠ same type
APH1B p.Gly174Ser Uncertain significance ★ ⚠ same type
APH1B p.Gly187Asp Uncertain significance ★ ⚠ same type
APH1B p.Gly187Ser 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/aph1b-p-phe40ser (accessed [today's date]).

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