Is DMAC2L p.Arg57Cys (c.169C>T) pathogenic?

DMAC2L p.Arg57Cys (c.169C>T) is classified Uncertain significance in DMAC2L (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-16). AlphaMissense: likely pathogenic (0.5696); Ultra-rare (popmax 0.0626%, afr).

How common is DMAC2L p.Arg57Cys (c.169C>T) in the general population?

DMAC2L p.Arg57Cys (c.169C>T) is ultra-rare (popmax 0.0626%, afr) (gnomAD).

What do computational predictors say about DMAC2L p.Arg57Cys (c.169C>T)?

AlphaMissense predicts likely pathogenic (score 0.5696) — an in-silico prediction, not a clinical call.

DMAC2L p.Arg57Cys

c.169C>T · rs139958711 · VCV3083001

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5696 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0626%, afr)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.5696	likely pathogenic
REVEL	0.718	pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 4,232 bp · p 0.63 · regional, not allelic
Overall
CADD	33.0	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 is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R72C vs ClinVar R57C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0626% African / African-American · 47/75,034 alleles

Filtering AF 0.0483% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0433%

Overall 0.00477% 77/1,614,130 alleles · ultra-rare exomes 51/1,461,860 · genomes 26/152,270 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0626%	1,596
Middle Eastern	0.0165%	6,062
Admixed American	0.0133%	7,503
Remaining individualsnot grpmax-eligible	0.0064%	15,626
East Asian	0.00223%	44,884
European (non-Finnish)	0.00136%	73,750

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: DMAC2L
Protein: p.Arg57Cys
Coding: c.169C>T
MANE Select: NM_001382507
dbSNP: rs139958711
Type: single nucleotide variant
Location: chr14:50322572 (GRCh38)
Gene constraint: LOEUF 1.315 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.27

Full DMAC2L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DMAC2L p.Arg57His Uncertain significance ★ same residue
L2HGDH p.Met1Val Pathogenic ★★ same type
L2HGDH c.140+3G>C Uncertain significance ★★ same type
L2HGDH p.Ala26Val Uncertain significance ★★ ⚠ same type
L2HGDH p.Ser41Asn Uncertain significance ★★ ⚠ same type
L2HGDH p.Ala20= Likely benign ★★ same type
L2HGDH p.Leu18Arg Benign/Likely benign ★★ same type
L2HGDH p.Ser23= Likely benign ★★ 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/dmac2l-p-arg57cys (accessed [today's date]).

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