Is USH2A p.Pro4006= (c.12018C>T) pathogenic?

USH2A p.Pro4006= (c.12018C>T) is classified Likely benign in USH2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-02). Very rare (popmax 0.00401%, afr).

How common is USH2A p.Pro4006= (c.12018C>T) in the general population?

USH2A p.Pro4006= (c.12018C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

USH2A p.Pro4006=

c.12018C>T · rs777267938 · VCV1147417

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.1	GERP -4.1
Overall
CADD	0.451	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,878 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00105% 17/1,613,984 alleles · very rare exomes 14/1,461,876 · genomes 3/152,108 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,959
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.0011%	90,773

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.Pro4006=
Coding: c.12018C>T
MANE Select: NM_206933
dbSNP: rs777267938
Type: single nucleotide variant
Location: chr1:215728078 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4006: the fibronectin type-iii 25 domain

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

Similar variants

USH2A p.Pro4006Ser Uncertain significance ★ ⚠ same residue
USH2A p.Pro4006Thr Uncertain significance ★ ⚠ same residue
USH2A c.12295-3T>A Pathogenic ★★★ same type
USH2A c.8559-2A>G Pathogenic ★★★ same type
USH2A c.8682-9A>G Pathogenic ★★★ same type
USH2A p.Ala4740Asp Pathogenic ★★★ ⚠ same type
USH2A p.Arg3905Cys Pathogenic ★★★ ⚠ same type
USH2A p.Arg4192Cys Likely pathogenic ★★★ ⚠ 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/ush2a-p-pro4006 (accessed [today's date]).

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