Is AAMDC p.Arg34Trp (c.100C>T) pathogenic?

AAMDC p.Arg34Trp (c.100C>T) is classified Uncertain significance in AAMDC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-22). AlphaMissense: ambiguous (0.3913); Ultra-rare (popmax 0.0167%, amr).

How common is AAMDC p.Arg34Trp (c.100C>T) in the general population?

AAMDC p.Arg34Trp (c.100C>T) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about AAMDC p.Arg34Trp (c.100C>T)?

AlphaMissense predicts ambiguous (score 0.3913) — an in-silico prediction, not a clinical call.

AAMDC p.Arg34Trp

c.100C>T · VCV3815621

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3913 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3913	ambiguous
REVEL	0.685	pathogenic-leaning
SaProt	LLR -13.54	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.75 · regional, not allelic
Overall
CADD	32.0	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 0.0167% Admixed American · 10/59,944 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00682%

Overall 0.00347% 56/1,613,700 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,994
East Asian	0.0156%	6,411
African / African-American	0.00401%	24,968
European (non-Finnish)	0.00305%	32,776

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.Arg34Trp
Coding: c.100C>T
MANE Select: NM_024684
Type: single nucleotide variant
Location: chr11:77842596 (GRCh38)
Gene constraint: LOEUF 1.571 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.78 · 2 PDB
Residue 34: the 'mth138-like domain' region; a β-strand

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

Similar variants

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
AAMDC p.Ile67Thr 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-arg34trp (accessed [today's date]).

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