Is ESM1 p.Arg184Cys (c.550C>T) pathogenic?

ESM1 p.Arg184Cys (c.550C>T) is classified Uncertain significance in ESM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-16). AlphaMissense: likely pathogenic (0.8418); Ultra-rare (popmax 0.0133%, afr).

How common is ESM1 p.Arg184Cys (c.550C>T) in the general population?

ESM1 p.Arg184Cys (c.550C>T) is ultra-rare (popmax 0.0133%, afr) (gnomAD).

What do computational predictors say about ESM1 p.Arg184Cys (c.550C>T)?

AlphaMissense predicts likely pathogenic (score 0.8418) — an in-silico prediction, not a clinical call.

ESM1 p.Arg184Cys

c.550C>T · rs542750498 · VCV3090452

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8418 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8418	likely pathogenic
REVEL	0.334	indeterminate
SaProt	LLR -7.75	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 6,182 bp · p 0.0029 · regional, not allelic
Overall
CADD	32.0	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 0.0133% African / African-American · 10/74,942 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.00112% 18/1,610,408 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0133%	7,494
South Asian	0.0033%	30,321
Remaining individualsnot grpmax-eligible	0.0016%	62,374
Finnishnot grpmax-eligible	0.00156%	64,028
European (non-Finnish)	0.000255%	392,240

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.Arg184Cys
Coding: c.550C>T
MANE Select: NM_007036
dbSNP: rs542750498
Type: single nucleotide variant
Location: chr5:54979337 (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.Arg184His 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-arg184cys (accessed [today's date]).

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