Is USH2A p.Pro1978Ser (c.5932C>T) pathogenic?

USH2A p.Pro1978Ser (c.5932C>T) is classified Benign/Likely benign in USH2A (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-01-27). AlphaMissense: ambiguous (0.4124); Rare (popmax 0.608%, afr); Associated with Usher syndrome type 2A.

What condition is associated with USH2A p.Pro1978Ser (c.5932C>T)?

USH2A p.Pro1978Ser (c.5932C>T) is associated with Usher syndrome type 2A, retinitis pigmentosa 39 (ClinVar).

How common is USH2A p.Pro1978Ser (c.5932C>T) in the general population?

USH2A p.Pro1978Ser (c.5932C>T) is rare (popmax 0.608%, afr) (gnomAD).

What do computational predictors say about USH2A p.Pro1978Ser (c.5932C>T)?

AlphaMissense predicts ambiguous (score 0.4124) — an in-silico prediction, not a clinical call.

USH2A p.Pro1978Ser

c.5932C>T · rs75698489 · VCV178652

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

AlphaMissense

ambiguous

0.4124 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.608%, afr)

Conditions

Usher syndrome type 2A

Computational evidence

Protein change
AlphaMissense	0.4124	ambiguous
REVEL	0.559	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.17, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	21.8	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 0.608% African / African-American · 456/74,992 alleles

Filtering AF 0.562% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.544%

Overall 0.0312% 504/1,613,916 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.608%	164
Admixed American	0.0483%	2,069
Remaining individualsnot grpmax-eligible	0.0288%	3,472
European (non-Finnish)	8.48e-05%	1,179,902

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.Pro1978Ser
Coding: c.5932C>T
MANE Select: NM_206933
dbSNP: rs75698489
Type: single nucleotide variant
Location: chr1:216070218 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1978: the fibronectin type-iii 6 domain; a UniProt-annotated variant site (in rp39; uncertain significance)

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

Disease context

Usher syndrome type 2A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinitis pigmentosa 39

Similar variants

USH2A p.Pro1978fs Pathogenic/Likely pathogenic ★★ same residue
USH2A p.Pro1978His Uncertain significance ★★ same residue
USH2A p.Pro1978= 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

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-pro1978ser (accessed [today's date]).

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