Is ESPN p.Ser612Trp (c.1835C>G) pathogenic?

ESPN p.Ser612Trp (c.1835C>G) is classified Uncertain significance in ESPN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-17). AlphaMissense: likely benign (0.1935); Very rare (popmax 8.99e-05%, nfe).

How common is ESPN p.Ser612Trp (c.1835C>G) in the general population?

ESPN p.Ser612Trp (c.1835C>G) is very rare (popmax 8.99e-05%, nfe) (gnomAD).

What do computational predictors say about ESPN p.Ser612Trp (c.1835C>G)?

AlphaMissense predicts likely benign (score 0.1935) — an in-silico prediction, not a clinical call.

ESPN p.Ser612Trp

c.1835C>G · VCV3906483

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1935 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.99e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1935	likely benign
REVEL	0.356	indeterminate
SaProt	LLR -8.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 1.4, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 11 kb · p 0.7 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.99e-05% European (non-Finnish) · 1/1,111,826 alleles

Overall 7.65e-05% 1/1,307,032 alleles · very rare

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.Ser612Trp
Coding: c.1835C>G
MANE Select: NM_031475
Type: single nucleotide variant
Location: chr1:6449011 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 612: 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-ser612trp (accessed [today's date]).

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