Is MAK p.Pro520Ser (c.1558C>T) pathogenic?

MAK p.Pro520Ser (c.1558C>T) is classified Benign/Likely benign in MAK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0727); Common (popmax 8.99%, amr) — too common for a highly-penetrant pathogenic allele; Associated with inherited retinal dystrophy.

What condition is associated with MAK p.Pro520Ser (c.1558C>T)?

MAK p.Pro520Ser (c.1558C>T) is associated with inherited retinal dystrophy (ClinVar).

What do computational predictors say about MAK p.Pro520Ser (c.1558C>T)?

AlphaMissense predicts likely benign (score 0.0727) — an in-silico prediction, not a clinical call.

MAK p.Pro520Ser

Q: How common is MAK p.Pro520Ser (c.1558C>T) in the general population?

MAK p.Pro520Ser (c.1558C>T) is common (popmax 8.99%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1558C>T · rs567083 · VCV354789

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0727 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 8.99%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.0727	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -5.68	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 0.41	GERP 2, phastCons 0.04
Regional constraint	o/e 0.90	unconstrained · MANE · 66 kb · p 0.0057 · regional, not allelic
Overall
CADD	7.122	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 8.99% Admixed American · 5,392/59,996 alleles

Filtering AF 8.79% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.7%

Overall 2.18% 35,240/1,613,856 alleles · common exomes 32,159/1,461,576 · genomes 3,081/152,280 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	8.99%	11
Finnishnot grpmax-eligible	4.3%	23
European (non-Finnish)	2.08%	48
Remaining individualsnot grpmax-eligible	1.65%	61
South Asian	1.19%	84
Middle Eastern	0.71%	141
African / African-American	0.441%	227
Ashkenazi Jewishnot grpmax-eligible	0.27%	370
East Asian	0.078%	1,282

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.Pro520Ser
Coding: c.1558C>T
MANE Select: NM_001242957
dbSNP: rs567083
Type: single nucleotide variant
Location: chr6:10775367 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.74
Residue 520: a UniProt-annotated variant site (in)

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

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAK p.Pro520= Likely benign ★★ same residue
MAK p.Asn130His Likely pathogenic ★★ same condition
MAK p.Gln351Ter Pathogenic/Likely pathogenic ★★ same condition
MAK p.Glu263Lys Uncertain significance ★★ ⚠ same condition
MAK p.His123Leu Uncertain significance ★★ ⚠ same condition
MAK p.Ile189Val Uncertain significance ★★ ⚠ same condition
MAK p.Lys402Thr Uncertain significance ★★ ⚠ same condition
MAK p.Met425Val 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-pro520ser (accessed [today's date]).

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