Is DMAC2 p.Leu217Val (c.649C>G) pathogenic?

DMAC2 p.Leu217Val (c.649C>G) is classified Uncertain significance in DMAC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-01). AlphaMissense: ambiguous (0.3685); Ultra-rare (popmax 0.022%, sas).

How common is DMAC2 p.Leu217Val (c.649C>G) in the general population?

DMAC2 p.Leu217Val (c.649C>G) is ultra-rare (popmax 0.022%, sas) (gnomAD).

What do computational predictors say about DMAC2 p.Leu217Val (c.649C>G)?

AlphaMissense predicts ambiguous (score 0.3685) — an in-silico prediction, not a clinical call.

DMAC2 p.Leu217Val

c.649C>G · VCV3840428

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3685 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.022%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3685	ambiguous
REVEL	0.228	benign-leaning
SaProt	LLR -9.24	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 7,665 bp · p 0.25 · regional, not allelic
Overall
CADD	24.4	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 0.022% South Asian · 20/91,094 alleles

Filtering AF 0.0145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00409% 66/1,614,050 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.022%	4,555
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0048%	20,827
European (non-Finnish)	0.00339%	29,501
African / African-American	0.00267%	37,469

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: DMAC2
Protein: p.Leu217Val
Coding: c.649C>G
MANE Select: NM_018035
Type: single nucleotide variant
Location: chr19:41432356 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.56

Full DMAC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DMAC2 p.His23Arg Likely benign ★★ same type
DMAC2 p.Ala193Thr Uncertain significance ★ ⚠ same type
DMAC2 p.Ala237Thr Uncertain significance ★ ⚠ same type
DMAC2 p.Ala27Val Uncertain significance ★ ⚠ same type
DMAC2 p.Ala86Thr Uncertain significance ★ ⚠ same type
DMAC2 p.Arg107Ser Uncertain significance ★ ⚠ same type
DMAC2 p.Arg146Gly Uncertain significance ★ ⚠ same type
DMAC2 p.Arg146His 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/dmac2-p-leu217val (accessed [today's date]).

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