Is MAP4 p.Ser427Tyr (c.1280C>A) pathogenic?

MAP4 p.Ser427Tyr (c.1280C>A) is classified Benign in MAP4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-25). AlphaMissense: likely benign (0.1232); Common (popmax 35.2%, mid) — too common for a highly-penetrant pathogenic allele; Associated with MAP4-related disorder.

What condition is associated with MAP4 p.Ser427Tyr (c.1280C>A)?

MAP4 p.Ser427Tyr (c.1280C>A) is associated with MAP4-related disorder (ClinVar).

What do computational predictors say about MAP4 p.Ser427Tyr (c.1280C>A)?

AlphaMissense predicts likely benign (score 0.1232) — an in-silico prediction, not a clinical call.

MAP4 p.Ser427Tyr

Q: How common is MAP4 p.Ser427Tyr (c.1280C>A) in the general population?

MAP4 p.Ser427Tyr (c.1280C>A) is common (popmax 35.2%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1280C>A · rs1060407 · VCV3059551

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1232 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 35.2%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MAP4-related disorder

Computational evidence

Protein change
AlphaMissense	0.1232	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -10.83	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 0.94, phastCons 0.95
Regional constraint	o/e 0.91	unconstrained · MANE · 123 kb · p 2.5e-05 · regional, not allelic
Overall
CADD	17.02	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 35.2% Middle Eastern · 2,135/6,062 alleles

Filtering AF 34% ClinGen BA1/BS1 input FAF95, joint · FAF99 33.7%

Overall 29.5% 475,477/1,613,946 alleles · common exomes 437,602/1,461,792 · genomes 37,875/152,154 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	35.2%	3
Ashkenazi Jewishnot grpmax-eligible	35.2%	3
Admixed American	34.2%	3
South Asian	34.2%	3
European (non-Finnish)	30.3%	3
Remaining individualsnot grpmax-eligible	29.9%	3
Amishnot grpmax-eligible	29.5%	3
East Asian	25.5%	4
Finnishnot grpmax-eligible	21.7%	5
African / African-American	12.7%	8

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: MAP4
Protein: p.Ser427Tyr
Coding: c.1280C>A
MANE Select: NM_001385682
dbSNP: rs1060407
Type: single nucleotide variant
Location: chr3:47916547 (GRCh38)
Gene constraint: LOEUF 0.512 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 43.03
Residue 427: a UniProt-annotated variant site (in); the '17 x 14 aa tandem repeats' region

Full MAP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

MAP4-related disorder

Similar variants

MAP4 c.292+2409G>A Likely benign same condition
MAP4 c.*100G>A Likely benign same condition
MAP4 c.*44G>A Likely benign same condition
MAP4 p.Ala2123= Likely benign same condition
MAP4 p.Ala2134= Likely benign same condition
MAP4 p.Ala437= Likely benign same condition
MAP4 p.Arg23Gln Benign same condition
MAP4 p.Arg23Trp Likely benign ⚠ 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/map4-p-ser427tyr (accessed [today's date]).

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