Is ESPNL p.Ile741Val (c.2221A>G) pathogenic?

ESPNL p.Ile741Val (c.2221A>G) is classified Uncertain significance in ESPNL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-25). AlphaMissense: ambiguous (0.4046); Absent from gnomAD v4.1.

How common is ESPNL p.Ile741Val (c.2221A>G) in the general population?

ESPNL p.Ile741Val (c.2221A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ESPNL p.Ile741Val (c.2221A>G)?

AlphaMissense predicts ambiguous (score 0.4046) — an in-silico prediction, not a clinical call.

ESPNL p.Ile741Val

c.2221A>G · VCV3510388

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4046 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,549,806)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4046	ambiguous
REVEL	0.208	benign-leaning
SaProt	LLR -5.71	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 2, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.0064 · regional, not allelic
Overall
CADD	23.1	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

No allele count reported in gnomAD v4.1 (AN 1,549,806). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ESPNL
Protein: p.Ile741Val
Coding: c.2221A>G
MANE Select: NM_194312
Type: single nucleotide variant
Location: chr2:238130935 (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.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
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-ile741val (accessed [today's date]).

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