Is ALG14 p.Val136Met (c.406G>A) pathogenic?

ALG14 p.Val136Met (c.406G>A) is classified Uncertain significance in ALG14 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-27). AlphaMissense: likely benign (0.1629); Ultra-rare (popmax 0.0758%, sas); Associated with Inborn genetic diseases.

What condition is associated with ALG14 p.Val136Met (c.406G>A)?

ALG14 p.Val136Met (c.406G>A) is associated with Inborn genetic diseases, congenital myasthenic syndrome 15 (ClinVar).

How common is ALG14 p.Val136Met (c.406G>A) in the general population?

ALG14 p.Val136Met (c.406G>A) is ultra-rare (popmax 0.0758%, sas) (gnomAD).

What do computational predictors say about ALG14 p.Val136Met (c.406G>A)?

AlphaMissense predicts likely benign (score 0.1629) — an in-silico prediction, not a clinical call.

ALG14 p.Val136Met

c.406G>A · rs374376710 · VCV835869

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1629 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0758%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1629	likely benign
REVEL	0.129	moderately benign-leaning
SaProt	LLR -7.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.29	GERP -3.8
Regional constraint	o/e 1.06	unconstrained · MANE · 90 kb · p 0.32 · regional, not allelic
Overall
CADD	7.412	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0758% South Asian · 69/91,084 alleles

Filtering AF 0.0613% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0561%

Overall 0.00712% 115/1,614,050 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0758%	1,320
Middle Eastern	0.0496%	2,018
Remaining individualsnot grpmax-eligible	0.0192%	5,208
African / African-American	0.016%	6,252
European (non-Finnish)	0.00161%	62,104

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: ALG14
Protein: p.Val136Met
Coding: c.406G>A
MANE Select: NM_144988
dbSNP: rs374376710
Type: single nucleotide variant
Location: chr1:95027143 (GRCh38)
Gene constraint: LOEUF 1.055 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.06
Residue 136: a UniProt-annotated variant site (in cms15)

Full ALG14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital myasthenic syndrome 15

Similar variants

ALG14 p.Arg104Gln Uncertain significance ★★ ⚠ same condition
ALG14 p.Arg109Gln Uncertain significance ★★ ⚠ same condition
ALG14 p.Arg109Trp Uncertain significance ★★ ⚠ same condition
ALG14 p.Asn61Asp Uncertain significance ★★ ⚠ same condition
ALG14 p.Asn61Ser Uncertain significance ★★ ⚠ same condition
ALG14 p.Asn82Ser Uncertain significance ★★ ⚠ same condition
ALG14 p.Glu110Lys Uncertain significance ★★ ⚠ same condition
ALG14 p.Glu179Lys Uncertain significance ★★ ⚠ same condition

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/alg14-p-val136met (accessed [today's date]).

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