Is AAMDC p.Val49Ala (c.146T>C) pathogenic?

AAMDC p.Val49Ala (c.146T>C) is classified Uncertain significance in AAMDC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). AlphaMissense: likely pathogenic (0.8906); Rare (popmax 0.265%, afr).

How common is AAMDC p.Val49Ala (c.146T>C) in the general population?

AAMDC p.Val49Ala (c.146T>C) is rare (popmax 0.265%, afr) (gnomAD).

What do computational predictors say about AAMDC p.Val49Ala (c.146T>C)?

AlphaMissense predicts likely pathogenic (score 0.8906) — an in-silico prediction, not a clinical call.

AAMDC p.Val49Ala

c.146T>C · VCV4212586

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8906 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.265%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8906	likely pathogenic
REVEL	0.614	indeterminate
SaProt	LLR -11.55	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 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.75 · regional, not allelic
Overall
CADD	25.2	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 0.265% African / African-American · 199/75,040 alleles

Filtering AF 0.235% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.223%

Overall 0.0141% 227/1,613,916 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.265%	377
Remaining individualsnot grpmax-eligible	0.0272%	3,676
Admixed American	0.0167%	6,001
European (non-Finnish)	8.48e-05%	1,179,874

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: AAMDC
Protein: p.Val49Ala
Coding: c.146T>C
MANE Select: NM_024684
Type: single nucleotide variant
Location: chr11:77869735 (GRCh38)
Gene constraint: LOEUF 1.571 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.78 · 2 PDB
Residue 49: the 'mth138-like domain' region

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

Similar variants

AAMDC p.Arg34Trp Uncertain significance ★ ⚠ same type
AAMDC p.Arg69Gln Uncertain significance ★ ⚠ same type
AAMDC p.Glu40Lys Uncertain significance ★ ⚠ same type
AAMDC p.Gly12Glu Uncertain significance ★ ⚠ same type
AAMDC p.Gly18Ala Uncertain significance ★ ⚠ same type
AAMDC p.Gly31Ala Uncertain significance ★ ⚠ same type
AAMDC p.Gly48Arg Uncertain significance ★ ⚠ same type
AAMDC p.Gly61Arg 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/aamdc-p-val49ala (accessed [today's date]).

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