Is ESPN p.Ile425Thr (c.1274T>C) pathogenic?

ESPN p.Ile425Thr (c.1274T>C) is classified Likely benign in ESPN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-10). AlphaMissense: likely benign (0.0513); Rare (popmax 0.163%, eas).

How common is ESPN p.Ile425Thr (c.1274T>C) in the general population?

ESPN p.Ile425Thr (c.1274T>C) is rare (popmax 0.163%, eas) (gnomAD).

What do computational predictors say about ESPN p.Ile425Thr (c.1274T>C)?

AlphaMissense predicts likely benign (score 0.0513) — an in-silico prediction, not a clinical call.

ESPN p.Ile425Thr

c.1274T>C · rs548336753 · VCV1660835

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0513 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.163%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0513	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -5.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.8	GERP -2.9
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 0.002 · regional, not allelic
Overall
CADD	0.002	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 0.163% East Asian · 73/44,696 alleles

Filtering AF 0.133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.122%

Overall 0.00635% 102/1,605,706 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.163%	612
Remaining individualsnot grpmax-eligible	0.0209%	4,776
South Asian	0.0122%	8,191
African / African-American	0.00134%	74,590
European (non-Finnish)	0.00034%	294,199

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.Ile425Thr
Coding: c.1274T>C
MANE Select: NM_031475
dbSNP: rs548336753
Type: single nucleotide variant
Location: chr1:6445745 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 425: 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-ile425thr (accessed [today's date]).

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