Is APH1A p.Val194Ala (c.581T>C) pathogenic?

APH1A p.Val194Ala (c.581T>C) is classified Uncertain significance in APH1A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-19). AlphaMissense: likely benign (0.1786); Very rare (popmax 0.00169%, nfe).

How common is APH1A p.Val194Ala (c.581T>C) in the general population?

APH1A p.Val194Ala (c.581T>C) is very rare (popmax 0.00169%, nfe) (gnomAD).

What do computational predictors say about APH1A p.Val194Ala (c.581T>C)?

AlphaMissense predicts likely benign (score 0.1786) — an in-silico prediction, not a clinical call.

APH1A p.Val194Ala

c.581T>C · VCV3413495

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1786 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1786	likely benign
REVEL	0.376	indeterminate
SaProt	LLR -9.76	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.21	donor gain · deltas
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 2,677 bp · p 4.4e-07 · regional, not allelic
Overall
CADD	26.1	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 0.00169% European (non-Finnish) · 20/1,180,032 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00124% 20/1,613,998 alleles · very rare

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: APH1A
Protein: p.Val194Ala
Coding: c.581T>C
MANE Select: NM_001077628
Type: single nucleotide variant
Location: chr1:150267103 (GRCh38)
Gene constraint: LOEUF 0.806 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.69 · 25 PDB
Residue 194: an α-helix

Full APH1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APH1A p.Ala37Ser Uncertain significance ★ ⚠ same type
APH1A p.Ala49Ser Uncertain significance ★ ⚠ same type
APH1A p.Arg109Gly Uncertain significance ★ ⚠ same type
APH1A p.Arg186Trp Uncertain significance ★ ⚠ same type
APH1A p.Arg241Gly Uncertain significance ★ ⚠ same type
APH1A p.Arg241His Uncertain significance ★ ⚠ same type
APH1A p.Arg66Trp Uncertain significance ★ ⚠ same type
APH1A p.Asp61Asn 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/aph1a-p-val194ala (accessed [today's date]).

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