Is MAK p.Ser448Pro (c.1342T>C) pathogenic?

MAK p.Ser448Pro (c.1342T>C) is classified Uncertain significance in MAK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-24). AlphaMissense: likely benign (0.0612); Ultra-rare (popmax 0.0111%, eas); Associated with Inborn genetic diseases.

What condition is associated with MAK p.Ser448Pro (c.1342T>C)?

MAK p.Ser448Pro (c.1342T>C) is associated with Inborn genetic diseases (ClinVar).

How common is MAK p.Ser448Pro (c.1342T>C) in the general population?

MAK p.Ser448Pro (c.1342T>C) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about MAK p.Ser448Pro (c.1342T>C)?

AlphaMissense predicts likely benign (score 0.0612) — an in-silico prediction, not a clinical call.

MAK p.Ser448Pro

c.1342T>C · rs769938480 · VCV1968990

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0612 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0612	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	LLR -7.40	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 0.048	GERP -3
Regional constraint	o/e 0.90	unconstrained · MANE · 66 kb · p 0.0057 · regional, not allelic
Overall
CADD	0.123	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 0.0111% East Asian · 5/44,902 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000434% 7/1,613,942 alleles · ultra-rare exomes 6/1,461,882 · genomes 1/152,060 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,980
South Asian	0.0022%	45,536

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: MAK
Protein: p.Ser448Pro
Coding: c.1342T>C
MANE Select: NM_001242957
dbSNP: rs769938480
Type: single nucleotide variant
Location: chr6:10784547 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.74
Residue 448: the 'disordered' region

Full MAK 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

Similar variants

MAK p.Ala532Gly Uncertain significance ★★ ⚠ same condition
MAK p.Arg163Lys Uncertain significance ★★ ⚠ same condition
MAK p.Arg237His Uncertain significance ★★ ⚠ same condition
MAK p.Arg395Cys Uncertain significance ★★ same condition
MAK p.Arg613Cys Uncertain significance ★★ ⚠ same condition
MAK p.Arg648Trp Uncertain significance ★★ ⚠ same condition
MAK p.Arg70Gly Uncertain significance ★★ ⚠ same condition
MAK p.Asn304Ile 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/mak-p-ser448pro (accessed [today's date]).

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