Is ESPNL p.Arg58Trp (c.172C>T) pathogenic?

ESPNL p.Arg58Trp (c.172C>T) is classified Uncertain significance in ESPNL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-02). AlphaMissense: likely benign (0.1374); Ultra-rare (popmax 0.0161%, amr).

How common is ESPNL p.Arg58Trp (c.172C>T) in the general population?

ESPNL p.Arg58Trp (c.172C>T) is ultra-rare (popmax 0.0161%, amr) (gnomAD).

What do computational predictors say about ESPNL p.Arg58Trp (c.172C>T)?

AlphaMissense predicts likely benign (score 0.1374) — an in-silico prediction, not a clinical call.

ESPNL p.Arg58Trp

c.172C>T · rs752090591 · VCV2394760

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1374 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0161%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1374	likely benign
REVEL	0.219	benign-leaning
SaProt	LLR -10.86	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.75	GERP -2, phastCons 0.16
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.0064 · regional, not allelic
Overall
CADD	24.9	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 0.0161% Admixed American · 8/49,542 alleles

Filtering AF 0.00802% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00233% 36/1,542,280 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0161%	6,193
East Asian	0.00475%	21,047
European (non-Finnish)	0.00209%	47,830
African / African-American	0.00138%	72,242
South Asian	0.00122%	81,734

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: ESPNL
Protein: p.Arg58Trp
Coding: c.172C>T
MANE Select: NM_194312
dbSNP: rs752090591
Type: single nucleotide variant
Location: chr2:238100591 (GRCh38)
Gene constraint: LOEUF 1.651 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.57

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

Similar variants

ESPNL p.Arg58Gln Uncertain significance ★ ⚠ same residue
ESPNL p.Arg167Gln Benign ★★ same type
ESPNL p.Arg351Cys Benign ★★ same type
ESPNL c.672+1G>A Uncertain significance ★ same type
ESPNL p.Ala112Ser Uncertain significance ★ ⚠ same type
ESPNL p.Ala144Asp Uncertain significance ★ ⚠ same type
ESPNL p.Ala144Thr Uncertain significance ★ ⚠ same type
ESPNL p.Ala145Thr 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/espnl-p-arg58trp (accessed [today's date]).

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