Is PREP p.Tyr101His (c.301T>C) pathogenic?

PREP p.Tyr101His (c.301T>C) is classified Uncertain significance in PREP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-17). AlphaMissense: ambiguous (0.391); Very rare (popmax 0.00834%, amr).

How common is PREP p.Tyr101His (c.301T>C) in the general population?

PREP p.Tyr101His (c.301T>C) is very rare (popmax 0.00834%, amr) (gnomAD).

What do computational predictors say about PREP p.Tyr101His (c.301T>C)?

AlphaMissense predicts ambiguous (score 0.391) — an in-silico prediction, not a clinical call.

PREP p.Tyr101His

c.301T>C · VCV4144102

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.391 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.391	ambiguous
REVEL	0.727	pathogenic-leaning
SaProt	LLR -8.97	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 1.8, phastCons 1
Overall
CADD	26.7	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 0.00834% Admixed American · 5/59,980 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00136% 22/1,613,676 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00834%	11,996
Remaining individualsnot grpmax-eligible	0.0032%	31,237
African / African-American	0.00133%	74,924
European (non-Finnish)	0.00119%	84,267

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: PREP
Protein: p.Tyr101His
Coding: c.301T>C
MANE Select: NM_014889 · reported on NM_002726
Type: single nucleotide variant
Location: chr6:105376209 (GRCh38)
Structure: AlphaFold pLDDT 94.44 · 8 PDB

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

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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/prep-p-tyr101his (accessed [today's date]).

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