Is ADM p.Arg89His (c.266G>A) pathogenic?

ADM p.Arg89His (c.266G>A) is classified Uncertain significance in ADM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-08). AlphaMissense: likely benign (0.0891); Very rare (popmax 0.000558%, nfe).

How common is ADM p.Arg89His (c.266G>A) in the general population?

ADM p.Arg89His (c.266G>A) is very rare (popmax 0.000558%, nfe) (gnomAD).

What do computational predictors say about ADM p.Arg89His (c.266G>A)?

AlphaMissense predicts likely benign (score 0.0891) — an in-silico prediction, not a clinical call.

ADM p.Arg89His

c.266G>A · VCV4638511

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0891 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000558%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0891	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -5.10	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 1.7	phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 937 bp · p 0.95 · regional, not allelic
Overall
CADD	17.3	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 0.000558% European (non-Finnish) · 6/1,075,042 alleles

Filtering AF 0.000201% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000132%

Overall 0.000446% 6/1,344,512 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: ADM
Protein: p.Arg89His
Coding: c.266G>A
MANE Select: NM_001124
Type: single nucleotide variant
Location: chr11:10306349 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.90 (gnomAD)
Structure: AlphaFold pLDDT 62.35 · 8 PDB

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

Similar variants

ADM p.Ser50Arg Benign ★★ same type
ADM p.Ala22Ser Uncertain significance ★ ⚠ same type
ADM p.Ala38Ser Uncertain significance ★ ⚠ same type
ADM p.Ala38Val Uncertain significance ★ ⚠ same type
ADM p.Ala87Val Uncertain significance ★ ⚠ same type
ADM p.Arg23Trp Uncertain significance ★ ⚠ same type
ADM p.Arg94Leu Uncertain significance ★ ⚠ same type
ADM p.Arg96Gly 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/adm-p-arg89his (accessed [today's date]).

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