Is ESPN p.Arg546Cys (c.1636C>T) pathogenic?

ESPN p.Arg546Cys (c.1636C>T) is classified Benign in ESPN (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1248); Common (popmax 55.1%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ESPN p.Arg546Cys (c.1636C>T)?

AlphaMissense predicts likely benign (score 0.1248) — an in-silico prediction, not a clinical call.

ESPN p.Arg546Cys

Q: How common is ESPN p.Arg546Cys (c.1636C>T) in the general population?

ESPN p.Arg546Cys (c.1636C>T) is common (popmax 55.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1636C>T · rs138198721 · VCV508563

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1248 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 55.1%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1248	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -7.84	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 -0.097	GERP -2.7, phastCons 0.001
Regional constraint	o/e 0.58	unconstrained · MANE · 3,146 bp · p 3.4e-10 · regional, not allelic
Overall
CADD	15.02	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 55.1% African / African-American · 35,386/64,216 alleles

Filtering AF 54.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 54.4%

Overall 9.31% 116,576/1,251,918 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	55.1%	2
Middle Eastern	12.8%	8
Admixed American	11%	9
Remaining individualsnot grpmax-eligible	10.4%	10
South Asian	9.07%	11
Ashkenazi Jewishnot grpmax-eligible	6.86%	15
European (non-Finnish)	6.73%	15
Amishnot grpmax-eligible	6.25%	16
Finnishnot grpmax-eligible	4.93%	20
East Asian	0.99%	101

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: ESPN
Protein: p.Arg546Cys
Coding: c.1636C>T
MANE Select: NM_031475
dbSNP: rs138198721
Type: single nucleotide variant
Location: chr1:6448812 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 546: the 'disordered' region

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

Similar variants

ESPN c.1464+1G>A Likely pathogenic ★★ same type
ESPN p.Ala139Thr Uncertain significance ★★ ⚠ same type
ESPN p.Ala23Thr Uncertain significance ★★ ⚠ same type
ESPN p.Ala484Thr Uncertain significance ★★ ⚠ same type
ESPN p.Ala591Val Uncertain significance ★★ ⚠ same type
ESPN p.Ala610Pro Uncertain significance ★★ ⚠ same type
ESPN p.Ala624Thr Uncertain significance ★★ ⚠ same type
ESPN p.Ala729Glu 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/espn-p-arg546cys (accessed [today's date]).

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