Is ESPNL p.Arg167Trp (c.499C>T) pathogenic?

ESPNL p.Arg167Trp (c.499C>T) is classified Uncertain significance in ESPNL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-02). AlphaMissense: likely benign (0.1967); Very rare (popmax 0.0068%, eas).

How common is ESPNL p.Arg167Trp (c.499C>T) in the general population?

ESPNL p.Arg167Trp (c.499C>T) is very rare (popmax 0.0068%, eas) (gnomAD).

What do computational predictors say about ESPNL p.Arg167Trp (c.499C>T)?

AlphaMissense predicts likely benign (score 0.1967) — an in-silico prediction, not a clinical call.

ESPNL p.Arg167Trp

c.499C>T · VCV4665378

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1967 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0068%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1967	likely benign
REVEL	0.21	benign-leaning
SaProt	LLR -11.71	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 0.17	GERP -0.33
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.0064 · regional, not allelic
Overall
CADD	21.7	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 0.0068% East Asian · 3/44,098 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00069% 11/1,594,058 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0068%	14,699
South Asian	0.00112%	88,962
European (non-Finnish)	0.000598%	167,174

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.Arg167Trp
Coding: c.499C>T
MANE Select: NM_194312
Type: single nucleotide variant
Location: chr2:238104669 (GRCh38)
Gene constraint: LOEUF 1.651 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.57
Residue 167: a UniProt-annotated variant site (in)

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

Similar variants

ESPNL p.Arg167Gln Benign ★★ same residue
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
ESPNL p.Ala159Thr 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-arg167trp (accessed [today's date]).

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