Is ADPRH p.Leu140Phe (c.418C>T) pathogenic?

ADPRH p.Leu140Phe (c.418C>T) is classified Uncertain significance in ADPRH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-09). AlphaMissense: ambiguous (0.3525); Very rare (popmax 0.00329%, sas).

How common is ADPRH p.Leu140Phe (c.418C>T) in the general population?

ADPRH p.Leu140Phe (c.418C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about ADPRH p.Leu140Phe (c.418C>T)?

AlphaMissense predicts ambiguous (score 0.3525) — an in-silico prediction, not a clinical call.

ADPRH p.Leu140Phe

c.418C>T · rs1444145370 · VCV2294545

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3525 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Computational evidence

Protein change
AlphaMissense	0.3525	ambiguous
REVEL	0.295	indeterminate
SaProt	LLR -11.82	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2.3, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 5,705 bp · p 0.22 · regional, not allelic
Overall
CADD	25.4	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 0.00329% South Asian · 3/91,084 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000205% 3/1,461,890 alleles · very 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: ADPRH
Protein: p.Leu140Phe
Coding: c.418C>T
MANE Select: NM_001125
dbSNP: rs1444145370
Type: single nucleotide variant
Location: chr3:119586404 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 98.46 · 4 PDB
Residue 140: an α-helix

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

Similar variants

ADPRH p.Ala13Gly Uncertain significance ★ ⚠ same type
ADPRH p.Ala182Thr Uncertain significance ★ ⚠ same type
ADPRH p.Ala293Thr Uncertain significance ★ ⚠ same type
ADPRH p.Ala296Thr Uncertain significance ★ ⚠ same type
ADPRH p.Ala310Ser Uncertain significance ★ ⚠ same type
ADPRH p.Ala341Thr Uncertain significance ★ ⚠ same type
ADPRH p.Ala64Val Uncertain significance ★ ⚠ same type
ADPRH p.Ala70Gly 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/adprh-p-leu140phe (accessed [today's date]).

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