Is PREP p.Thr637Ser (c.1910C>G) pathogenic?

PREP p.Thr637Ser (c.1910C>G) is classified Uncertain significance in PREP (ClinVar, Single submitter, 2 submitters; last evaluated 2025-08-05). AlphaMissense: likely pathogenic (0.8783); Ultra-rare (popmax 0.0506%, afr).

How common is PREP p.Thr637Ser (c.1910C>G) in the general population?

PREP p.Thr637Ser (c.1910C>G) is ultra-rare (popmax 0.0506%, afr) (gnomAD).

What do computational predictors say about PREP p.Thr637Ser (c.1910C>G)?

AlphaMissense predicts likely pathogenic (score 0.8783) — an in-silico prediction, not a clinical call.

PREP p.Thr637Ser

c.1910C>G · VCV4144106

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8783 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0506%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8783	likely pathogenic · top 9% in PREP
REVEL	0.616	indeterminate
SaProt	LLR -8.09	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Overall
CADD	27.2	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 0.0506% African / African-American · 38/75,080 alleles

Filtering AF 0.0379% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0334%

Overall 0.00235% 38/1,614,236 alleles · ultra-rare

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.Thr637Ser
Coding: c.1910C>G
MANE Select: NM_014889 · reported on NM_002726
Type: single nucleotide variant
Location: chr6:105278367 (GRCh38)
Structure: AlphaFold pLDDT 94.44 · 8 PDB
Residue 637: an α-helix

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

Similar variants

PITRM1 p.Thr931Met Pathogenic/Likely pathogenic ★★ same type
PITRM1 p.Ala1003Thr Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala559Val Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala887Val Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala942Val Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala965Thr Uncertain significance ★★ ⚠ same type
PITRM1 p.Arg32Trp Uncertain significance ★★ ⚠ same type
PITRM1 p.Arg545Gln Uncertain significance ★★ ⚠ 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/prep-p-thr637ser (accessed [today's date]).

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