Is ESPN p.Ala173Val (c.518C>T) pathogenic?

ESPN p.Ala173Val (c.518C>T) is classified Benign/Likely benign in ESPN (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-06-13). AlphaMissense: ambiguous (0.5241); Ultra-rare (popmax 0.0373%, mid).

How common is ESPN p.Ala173Val (c.518C>T) in the general population?

ESPN p.Ala173Val (c.518C>T) is ultra-rare (popmax 0.0373%, mid) (gnomAD).

What do computational predictors say about ESPN p.Ala173Val (c.518C>T)?

AlphaMissense predicts ambiguous (score 0.5241) — an in-silico prediction, not a clinical call.

ESPN p.Ala173Val

c.518C>T · rs368890910 · VCV1214312

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5241 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0373%, mid)

Computational evidence

Protein change
AlphaMissense	0.5241	ambiguous
REVEL	0.374	indeterminate
SaProt	LLR -5.69	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 0.002 · regional, not allelic
Overall
CADD	29.9	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 0.0373% Middle Eastern · 2/5,356 alleles

Filtering AF 0.0165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0132%

Overall 0.00973% 151/1,551,306 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.293%	341
Middle Easterngrpmax	0.0373%	2,678
Admixed American	0.0273%	3,659
Remaining individualsnot grpmax-eligible	0.0266%	3,754
South Asian	0.00474%	21,083
European (non-Finnish)	0.0027%	37,019

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala173Val
Coding: c.518C>T
MANE Select: NM_031475
dbSNP: rs368890910
Type: single nucleotide variant
Location: chr1:6440283 (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-ala173val (accessed [today's date]).

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