Is USH2A p.Pro4818Leu (c.14453C>T) pathogenic?

USH2A p.Pro4818Leu (c.14453C>T) is classified Pathogenic/Likely pathogenic in USH2A (ClinVar, Multiple submitters, 19 submitters; last evaluated 2026-01-14). AlphaMissense: likely benign (0.1519); Ultra-rare (popmax 0.0275%, sas); Associated with Monogenic hearing loss.

What condition is associated with USH2A p.Pro4818Leu (c.14453C>T)?

USH2A p.Pro4818Leu (c.14453C>T) is associated with Monogenic hearing loss, Usher syndrome type 2A, retinitis pigmentosa 39 (ClinVar).

How common is USH2A p.Pro4818Leu (c.14453C>T) in the general population?

USH2A p.Pro4818Leu (c.14453C>T) is ultra-rare (popmax 0.0275%, sas) (gnomAD).

What do computational predictors say about USH2A p.Pro4818Leu (c.14453C>T)?

AlphaMissense predicts likely benign (score 0.1519) — an in-silico prediction, not a clinical call.

USH2A p.Pro4818Leu

c.14453C>T · rs143344549 · VCV504509

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 19 submitters

AlphaMissense

likely benign

0.1519 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0275%, sas)

Conditions

Monogenic hearing loss

Computational evidence

Protein change
AlphaMissense	0.1519	likely benign ⚠ discordant with ClinVar
REVEL	0.508	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0275% South Asian · 25/91,074 alleles

Filtering AF 0.019% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0163%

Overall 0.00669% 108/1,614,148 alleles · ultra-rare exomes 91/1,461,882 · genomes 17/152,266 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0275%	3,643
African / African-American	0.024%	4,168
Middle Eastern	0.0165%	6,062
Admixed American	0.0117%	8,575
European (non-Finnish)	0.00483%	20,702

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: USH2A
Protein: p.Pro4818Leu
Coding: c.14453C>T
MANE Select: NM_206933
dbSNP: rs143344549
Type: single nucleotide variant
Location: chr1:215648657 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4818: a UniProt-annotated variant site (in ush2a); the fibronectin type-iii 33 domain

Full USH2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Monogenic hearing loss

Also linked: Usher syndrome type 2A retinitis pigmentosa 39 inherited retinal dystrophy Usher syndrome

Similar variants

USH2A p.Pro4818= Benign/Likely benign ★★ same residue
USH2A c.12295-3T>A Pathogenic ★★★ same condition
USH2A c.8559-2A>G Pathogenic ★★★ same condition
USH2A c.8682-9A>G Pathogenic ★★★ same condition
USH2A p.Ala4740Asp Pathogenic ★★★ ⚠ same condition
USH2A p.Arg3905Cys Pathogenic ★★★ ⚠ same condition
USH2A p.Arg4192Cys Likely pathogenic ★★★ ⚠ same condition
USH2A p.Asn346His Pathogenic ★★★ 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/ush2a-p-pro4818leu (accessed [today's date]).

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