Is APH1A p.Arg241His (c.722G>A) pathogenic?

APH1A p.Arg241His (c.722G>A) is classified Uncertain significance in APH1A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely benign (0.0783); Very rare (popmax 0.00534%, afr).

How common is APH1A p.Arg241His (c.722G>A) in the general population?

APH1A p.Arg241His (c.722G>A) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about APH1A p.Arg241His (c.722G>A)?

AlphaMissense predicts likely benign (score 0.0783) — an in-silico prediction, not a clinical call.

APH1A p.Arg241His

c.722G>A · VCV4828854

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0783 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0783	likely benign
REVEL	0.123	moderately benign-leaning
SaProt	LLR -7.72	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 2.1	GERP 0.75, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 2,677 bp · p 4.4e-07 · regional, not allelic
Overall
CADD	22.6	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 0.00534% African / African-American · 4/74,902 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000805% 13/1,613,976 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,726
Admixed American	0.00333%	29,993
East Asian	0.00223%	44,892
South Asian	0.0022%	45,537
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	0.000254%	393,340

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.Arg241His
Coding: c.722G>A
MANE Select: NM_001077628
Type: single nucleotide variant
Location: chr1:150266544 (GRCh38)
Gene constraint: LOEUF 0.806 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.69 · 25 PDB
Residue 241: a turn

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

Similar variants

APH1A p.Arg241Gly Uncertain significance ★ ⚠ same residue
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.Arg66Trp Uncertain significance ★ ⚠ same type
APH1A p.Asp61Asn Uncertain significance ★ ⚠ same type
APH1A p.Gly70Ser 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-arg241his (accessed [today's date]).

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