Is ESPN p.Ser342Phe (c.1025C>T) pathogenic?

ESPN p.Ser342Phe (c.1025C>T) is classified Uncertain significance in ESPN (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-08-19). AlphaMissense: likely benign (0.2729); Ultra-rare (popmax 0.0383%, amr); Associated with Usher syndrome, type 1M.

What condition is associated with ESPN p.Ser342Phe (c.1025C>T)?

ESPN p.Ser342Phe (c.1025C>T) is associated with Usher syndrome, type 1M, inherited retinal dystrophy (ClinVar).

How common is ESPN p.Ser342Phe (c.1025C>T) in the general population?

ESPN p.Ser342Phe (c.1025C>T) is ultra-rare (popmax 0.0383%, amr) (gnomAD).

What do computational predictors say about ESPN p.Ser342Phe (c.1025C>T)?

AlphaMissense predicts likely benign (score 0.2729) — an in-silico prediction, not a clinical call.

ESPN p.Ser342Phe

c.1025C>T · rs199502924 · VCV228668

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.2729 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0383%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Usher syndrome, type 1M

Computational evidence

Protein change
AlphaMissense	0.2729	likely benign
REVEL	0.578	indeterminate
SaProt	LLR -6.08	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 7.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 0.002 · regional, not allelic
Overall
CADD	24.8	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 0.0383% Admixed American · 23/60,030 alleles

Filtering AF 0.0261% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.00904% 146/1,614,224 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.128%	779
Admixed Americangrpmax	0.0383%	2,610
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0144%	6,945
European (non-Finnish)	0.00619%	16,165
African / African-American	0.00133%	75,062

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.Ser342Phe
Coding: c.1025C>T
MANE Select: NM_031475
dbSNP: rs199502924
Type: single nucleotide variant
Location: chr1:6444515 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 342: the 'disordered' region; a modified residue (phosphoserine)

Full ESPN gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Usher syndrome, type 1M — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: inherited retinal dystrophy

Similar variants

ESPN p.Ser342= Likely benign ★★ same residue
ESPN p.Arg113His Uncertain significance ★★ same condition
ESPN p.Arg335Cys Uncertain significance ★★ same condition
ESPN p.Asp744Asn Uncertain significance ★★ ⚠ same condition
ESPN p.Ser312Leu Uncertain significance ★★ ⚠ same condition
ESPN p.Ser362Leu Uncertain significance ★★ ⚠ same condition
ESPN p.Ser690Leu Uncertain significance ★★ ⚠ same condition
ESPN p.Val165Met 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-ser342phe (accessed [today's date]).

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