Is DOLK p.Phe372Ile (c.1114T>A) pathogenic?

DOLK p.Phe372Ile (c.1114T>A) is classified Conflicting classifications of pathogenicity in DOLK (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1451); Rare (popmax 0.206%, afr); Associated with DK1-congenital disorder of glycosylation.

What condition is associated with DOLK p.Phe372Ile (c.1114T>A)?

DOLK p.Phe372Ile (c.1114T>A) is associated with DK1-congenital disorder of glycosylation (ClinVar).

How common is DOLK p.Phe372Ile (c.1114T>A) in the general population?

DOLK p.Phe372Ile (c.1114T>A) is rare (popmax 0.206%, afr) (gnomAD).

How is DK1-CDG inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DOLK p.Phe372Ile (c.1114T>A)?

AlphaMissense predicts likely benign (score 0.1451) — an in-silico prediction, not a clinical call.

DOLK p.Phe372Ile

c.1114T>A · rs146395561 · VCV388259

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1451 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.206%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DK1-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.1451	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -7.18	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 8	GERP 0.61, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 1,613 bp · p 0.00089 · regional, not allelic
Overall
CADD	19.36	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 0.206% African / African-American · 155/75,070 alleles

Filtering AF 0.18% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.17%

Overall 0.0108% 174/1,614,260 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.206%	484
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.016%	6,251
Admixed American	0.00833%	12,005
European (non-Finnish)	0.000169%	590,030

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: DOLK
Protein: p.Phe372Ile
Coding: c.1114T>A
MANE Select: NM_014908
dbSNP: rs146395561
Type: single nucleotide variant
Location: chr9:128946190 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.37
Residue 372: a UniProt-annotated variant site (in cdg1m)

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

Disease context

DK1-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For DK1-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

DOLK p.Phe372= Likely benign ★ same residue
DOLK p.His408Asp Pathogenic/Likely pathogenic ★★ same condition
DOLK p.Met1Ile Pathogenic/Likely pathogenic ★★ same condition
DOLK p.Met1Thr Pathogenic/Likely pathogenic ★★ same condition
DOLK c.-194G>T Uncertain significance ★★ same condition
DOLK c.-22G>A Uncertain significance ★★ same condition
DOLK c.-269G>T Uncertain significance ★★ same condition
DOLK p.Ala115Val 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/dolk-p-phe372ile (accessed [today's date]).

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