Is ESPNL p.Arg66Trp (c.196C>T) pathogenic?

ESPNL p.Arg66Trp (c.196C>T) is classified Uncertain significance in ESPNL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-26). AlphaMissense: likely benign (0.1568); Ultra-rare (popmax 0.0633%, nfe).

How common is ESPNL p.Arg66Trp (c.196C>T) in the general population?

ESPNL p.Arg66Trp (c.196C>T) is ultra-rare (popmax 0.0633%, nfe) (gnomAD).

What do computational predictors say about ESPNL p.Arg66Trp (c.196C>T)?

AlphaMissense predicts likely benign (score 0.1568) — an in-silico prediction, not a clinical call.

ESPNL p.Arg66Trp

c.196C>T · VCV4019792

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1568 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0633%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1568	likely benign
REVEL	0.287	benign-leaning
SaProt	LLR -13.67	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 1.5	GERP 1.7, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.0064 · regional, not allelic
Overall
CADD	25.2	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 0.0633% European (non-Finnish) · 715/1,129,108 alleles

Filtering AF 0.0594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0579%

Overall 0.0532% 799/1,501,184 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0633%	1,579
Remaining individualsnot grpmax-eligible	0.057%	1,753
African / African-American	0.0536%	1,865
Admixed American	0.0225%	4,454
East Asian	0.00493%	20,277
Finnishnot grpmax-eligible	0.0019%	52,610

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.Arg66Trp
Coding: c.196C>T
MANE Select: NM_194312
Type: single nucleotide variant
Location: chr2:238100615 (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.Arg66Gln 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-arg66trp (accessed [today's date]).

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