Is AMDHD1 p.Val44Leu (c.130G>T) pathogenic?

AMDHD1 p.Val44Leu (c.130G>T) is classified Uncertain significance in AMDHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-13). AlphaMissense: likely benign (0.2145); Ultra-rare (popmax 0.0147%, afr).

How common is AMDHD1 p.Val44Leu (c.130G>T) in the general population?

AMDHD1 p.Val44Leu (c.130G>T) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

What do computational predictors say about AMDHD1 p.Val44Leu (c.130G>T)?

AlphaMissense predicts likely benign (score 0.2145) — an in-silico prediction, not a clinical call.

AMDHD1 p.Val44Leu

c.130G>T · rs903420255 · VCV2211314

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2145 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2145	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -4.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.9	GERP 1.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 24 kb · p 0.15 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0147% African / African-American · 10/67,842 alleles

Filtering AF 0.00793% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00601%

Overall 0.00143% 21/1,468,580 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,784
Remaining individualsnot grpmax-eligible	0.00879%	11,373
European (non-Finnish)	0.000539%	185,585

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: AMDHD1
Protein: p.Val44Leu
Coding: c.130G>T
MANE Select: NM_152435
dbSNP: rs903420255
Type: single nucleotide variant
Location: chr12:95943528 (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-val44leu (accessed [today's date]).

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