Is ESM1 p.Arg184His (c.551G>A) pathogenic?

ESM1 p.Arg184His (c.551G>A) is classified Uncertain significance in ESM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: ambiguous (0.4626); Very rare (popmax 0.00267%, afr).

How common is ESM1 p.Arg184His (c.551G>A) in the general population?

ESM1 p.Arg184His (c.551G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ESM1 p.Arg184His (c.551G>A)?

AlphaMissense predicts ambiguous (score 0.4626) — an in-silico prediction, not a clinical call.

ESM1 p.Arg184His

c.551G>A · VCV4665346

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4626 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4626	ambiguous
REVEL	0.272	benign-leaning
SaProt	LLR -6.75	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 6,182 bp · p 0.0029 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,844 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000435% 7/1,610,424 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,422
South Asian	0.0011%	90,956
European (non-Finnish)	0.00034%	294,220

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: ESM1
Protein: p.Arg184His
Coding: c.551G>A
MANE Select: NM_007036
Type: single nucleotide variant
Location: chr5:54979336 (GRCh38)
Gene constraint: LOEUF 0.862 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 72.15

Full ESM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ESM1 p.Arg184Cys Uncertain significance ★ ⚠ same residue
ESM1 p.Thr150= Benign ★★ same type
ESM1 p.Arg124Gly Uncertain significance ★ ⚠ same type
ESM1 p.Asp158Asn Uncertain significance ★ ⚠ same type
ESM1 p.Asp158Tyr Uncertain significance ★ ⚠ same type
ESM1 p.Cys32Gly Uncertain significance ★ ⚠ same type
ESM1 p.Gly120Asp Uncertain significance ★ ⚠ same type
ESM1 p.Ile121Val 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/esm1-p-arg184his (accessed [today's date]).

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