Is AMDHD2 p.Thr109Ile (c.326C>T) pathogenic?

AMDHD2 p.Thr109Ile (c.326C>T) is classified Uncertain significance in AMDHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-14). AlphaMissense: likely pathogenic (0.9735); Very rare (popmax 8.52e-05%, nfe).

How common is AMDHD2 p.Thr109Ile (c.326C>T) in the general population?

AMDHD2 p.Thr109Ile (c.326C>T) is very rare (popmax 8.52e-05%, nfe) (gnomAD).

What do computational predictors say about AMDHD2 p.Thr109Ile (c.326C>T)?

AlphaMissense predicts likely pathogenic (score 0.9735) — an in-silico prediction, not a clinical call.

AMDHD2 p.Thr109Ile

c.326C>T · rs764928929 · VCV2600870

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9735 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.52e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9735	likely pathogenic · top 5% in AMDHD2
REVEL	0.48	indeterminate
SaProt	LLR -14.46	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.47, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 9,101 bp · p 0.046 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.52e-05% European (non-Finnish) · 1/1,173,176 alleles

Overall 6.89e-05% 1/1,451,668 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: AMDHD2
Protein: p.Thr109Ile
Coding: c.326C>T
MANE Select: NM_001330449
dbSNP: rs764928929
Type: single nucleotide variant
Location: chr16:2521089 (GRCh38)
Gene constraint: LOEUF 0.868 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.49 · 2 PDB
Residue 109: a β-strand

Full AMDHD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ATP6V0C p.Pro49Leu Likely pathogenic ★★ same type
ATP6V0C p.Ala95Thr Likely pathogenic ★ same type
AMDHD2 c.970+10C>T Uncertain significance ★ same type
AMDHD2 c.970+19T>G Uncertain significance ★ same type
AMDHD2 c.970+40C>T Uncertain significance ★ same type
AMDHD2 c.970+7G>A Uncertain significance ★ same type
AMDHD2 c.971-18G>A Uncertain significance ★ same type
AMDHD2 c.971-27C>G 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/amdhd2-p-thr109ile (accessed [today's date]).

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