Is DMAC2L p.Leu77Phe (c.229C>T) pathogenic?

DMAC2L p.Leu77Phe (c.229C>T) is classified Uncertain significance in DMAC2L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-04). AlphaMissense: likely pathogenic (0.7636); Very rare (popmax 0.00167%, amr).

How common is DMAC2L p.Leu77Phe (c.229C>T) in the general population?

DMAC2L p.Leu77Phe (c.229C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about DMAC2L p.Leu77Phe (c.229C>T)?

AlphaMissense predicts likely pathogenic (score 0.7636) — an in-silico prediction, not a clinical call.

DMAC2L p.Leu77Phe

c.229C>T · VCV4012192

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7636 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.7636	likely pathogenic
REVEL	0.785	moderately pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 4,232 bp · p 0.63 · regional, not allelic
Overall
CADD	25.4	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L92F vs ClinVar L77F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,022 alleles

Overall 0.000137% 2/1,461,890 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,022
European (non-Finnish)	8.47e-05%	1,180,030

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.Leu77Phe
Coding: c.229C>T
MANE Select: NM_001382507
Type: single nucleotide variant
Location: chr14:50322632 (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

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
L2HGDH p.Thr46Ile 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-leu77phe (accessed [today's date]).

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