Is ESPN p.Val723Met (c.2167G>A) pathogenic?

ESPN p.Val723Met (c.2167G>A) is classified Uncertain significance in ESPN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-20). AlphaMissense: likely benign (0.1208); Ultra-rare (popmax 0.0168%, mid); Associated with Inborn genetic diseases.

What condition is associated with ESPN p.Val723Met (c.2167G>A)?

ESPN p.Val723Met (c.2167G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ESPN p.Val723Met (c.2167G>A) in the general population?

ESPN p.Val723Met (c.2167G>A) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

What do computational predictors say about ESPN p.Val723Met (c.2167G>A)?

AlphaMissense predicts likely benign (score 0.1208) — an in-silico prediction, not a clinical call.

ESPN p.Val723Met

c.2167G>A · rs370514263 · VCV1394604

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1208 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1208	likely benign
REVEL	0.288	benign-leaning
SaProt	LLR -8.03	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 6.9	GERP 0.21, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 11 kb · p 0.7 · regional, not allelic
Overall
CADD	17.93	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 0.0168% Middle Eastern · 1/5,970 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00395%

Overall 0.00124% 20/1,610,614 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,970
East Asian	0.0134%	7,462
Admixed American	0.00334%	29,896
South Asian	0.00221%	45,207
African / African-American	0.00133%	74,998
European (non-Finnish)	0.000679%	147,344

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.Val723Met
Coding: c.2167G>A
MANE Select: NM_031475
dbSNP: rs370514263
Type: single nucleotide variant
Location: chr1:6451938 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ESPN p.Val723Leu Uncertain significance ★ ⚠ same residue
ESPN p.Ala139Thr Uncertain significance ★★ ⚠ same condition
ESPN p.Ala23Thr Uncertain significance ★★ ⚠ same condition
ESPN p.Ala484Thr Uncertain significance ★★ ⚠ same condition
ESPN p.Ala729Glu Uncertain significance ★★ ⚠ same condition
ESPN p.Arg113His Uncertain significance ★★ ⚠ same condition
ESPN p.Arg335Cys Uncertain significance ★★ ⚠ same condition
ESPN p.Arg339Gln Uncertain significance ★★ ⚠ same condition

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-val723met (accessed [today's date]).

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