Is AMBN p.Arg222His (c.665G>A) pathogenic?

AMBN p.Arg222His (c.665G>A) is classified Uncertain significance in AMBN (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-16). AlphaMissense: likely benign (0.0912); Ultra-rare (popmax 0.0888%, nfe).

How common is AMBN p.Arg222His (c.665G>A) in the general population?

AMBN p.Arg222His (c.665G>A) is ultra-rare (popmax 0.0888%, nfe) (gnomAD).

What do computational predictors say about AMBN p.Arg222His (c.665G>A)?

AlphaMissense predicts likely benign (score 0.0912) — an in-silico prediction, not a clinical call.

AMBN p.Arg222His

c.665G>A · rs142755020 · VCV2383207

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0912 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0888%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0912	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -6.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.28 · evaluated, not missing
Pangolin	Δ0.23	loss · gain 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 0.99	GERP 1, phastCons 0.88
Regional constraint	o/e 1.04	unconstrained · MANE · 14 kb · p 0.31 · regional, not allelic
Overall
CADD	17.58	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 0.0888% European (non-Finnish) · 1,048/1,179,698 alleles

Filtering AF 0.0843% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0825%

Overall 0.0698% 1,126/1,613,388 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0888%	1,126
Remaining individualsnot grpmax-eligible	0.0753%	1,329
Admixed American	0.02%	4,998
African / African-American	0.0187%	5,355
Middle Eastern	0.0165%	6,048
East Asian	0.00223%	44,780
South Asian	0.0022%	45,520
Finnishnot grpmax-eligible	0.00156%	63,920

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: AMBN
Protein: p.Arg222His
Coding: c.665G>A
MANE Select: NM_016519
dbSNP: rs142755020
Type: single nucleotide variant
Location: chr4:70603276 (GRCh38)
Gene constraint: LOEUF 1.345 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 44.05

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

Similar variants

AMBN p.Arg222Cys Uncertain significance ★ ⚠ same residue
AMBN p.Ser70Ter Uncertain significance ★★ same type
AMBN p.Gly268Arg Likely benign ★★ same type
AMBN p.His294Gln Benign/Likely benign ★★ same type
AMBN p.Leu354Pro Benign ★★ same type
AMBN p.Val378Ile Benign ★★ same type
AMBN c.295-2A>C Likely pathogenic ★ same type
AMBN c.15+1G>A 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/ambn-p-arg222his (accessed [today's date]).

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