Is AMDHD1 p.Pro345Leu (c.1034C>T) pathogenic?

AMDHD1 p.Pro345Leu (c.1034C>T) is classified Uncertain significance in AMDHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). AlphaMissense: ambiguous (0.4602); Absent from gnomAD v4.1.

How common is AMDHD1 p.Pro345Leu (c.1034C>T) in the general population?

AMDHD1 p.Pro345Leu (c.1034C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AMDHD1 p.Pro345Leu (c.1034C>T)?

AlphaMissense predicts ambiguous (score 0.4602) — an in-silico prediction, not a clinical call.

AMDHD1 p.Pro345Leu

c.1034C>T · VCV4090823

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4602 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.4602	ambiguous
REVEL	0.621	indeterminate
SaProt	LLR -9.27	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 24 kb · p 0.15 · regional, not allelic
Overall
CADD	28.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AMDHD1
Protein: p.Pro345Leu
Coding: c.1034C>T
MANE Select: NM_152435
Type: single nucleotide variant
Location: chr12:95966349 (GRCh38)
Gene constraint: LOEUF 1.381 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.23

Full AMDHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AMDHD1 p.Ala107Gly Uncertain significance ★ ⚠ same type
AMDHD1 p.Ala20Asp Uncertain significance ★ ⚠ same type
AMDHD1 p.Ala302Pro Uncertain significance ★ ⚠ same type
AMDHD1 p.Ala339Val Uncertain significance ★ ⚠ same type
AMDHD1 p.Ala35Ser Uncertain significance ★ ⚠ same type
AMDHD1 p.Ala364Asp Uncertain significance ★ ⚠ same type
AMDHD1 p.Ala373Val Uncertain significance ★ ⚠ same type
AMDHD1 p.Ala56Pro 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/amdhd1-p-pro345leu (accessed [today's date]).

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