Is ESPN p.Ala248Val (c.743C>T) pathogenic?

ESPN p.Ala248Val (c.743C>T) is classified Uncertain significance in ESPN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-10). AlphaMissense: likely pathogenic (0.8518); Ultra-rare (popmax 0.0691%, mid).

How common is ESPN p.Ala248Val (c.743C>T) in the general population?

ESPN p.Ala248Val (c.743C>T) is ultra-rare (popmax 0.0691%, mid) (gnomAD).

What do computational predictors say about ESPN p.Ala248Val (c.743C>T)?

AlphaMissense predicts likely pathogenic (score 0.8518) — an in-silico prediction, not a clinical call.

ESPN p.Ala248Val

c.743C>T · rs769311195 · VCV2157159

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8518 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0691%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8518	likely pathogenic
REVEL	0.471	indeterminate
SaProt	LLR -11.86	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.20	donor gain · deltas
Constraint at this position
Conservation	phyloP 7.4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 0.002 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0691% Middle Eastern · 3/4,340 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00999%

Overall 0.0011% 17/1,539,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0691%	1,447
Remaining individualsnot grpmax-eligible	0.00668%	14,971
East Asian	0.00246%	40,624
Admixed American	0.00191%	52,242
African / African-American	0.00139%	71,760
South Asian	0.0012%	83,444
European (non-Finnish)	0.000521%	191,954

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.Ala248Val
Coding: c.743C>T
MANE Select: NM_031475
dbSNP: rs769311195
Type: single nucleotide variant
Location: chr1:6440693 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76

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-ala248val (accessed [today's date]).

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