Is MAP4 p.Thr216Met (c.647C>T) pathogenic?

MAP4 p.Thr216Met (c.647C>T) is classified Benign in MAP4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-06-06). AlphaMissense: likely benign (0.102); Low-frequency (popmax 1.57%, afr); Associated with MAP4-related disorder.

What condition is associated with MAP4 p.Thr216Met (c.647C>T)?

MAP4 p.Thr216Met (c.647C>T) is associated with MAP4-related disorder (ClinVar).

How common is MAP4 p.Thr216Met (c.647C>T) in the general population?

MAP4 p.Thr216Met (c.647C>T) is low-frequency (popmax 1.57%, afr) (gnomAD).

What do computational predictors say about MAP4 p.Thr216Met (c.647C>T)?

AlphaMissense predicts likely benign (score 0.102) — an in-silico prediction, not a clinical call.

MAP4 p.Thr216Met

c.647C>T · rs76333690 · VCV3044324

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.102 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.57%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MAP4-related disorder

Computational evidence

Protein change
AlphaMissense	0.102	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -7.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.48 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.61	GERP -1.6
Regional constraint	o/e 0.91	unconstrained · MANE · 123 kb · p 2.5e-05 · regional, not allelic
Overall
CADD	16.41	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 1.57% African / African-American · 1,179/74,880 alleles

Filtering AF 1.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.47%

Overall 0.0871% 1,402/1,608,914 alleles · low-frequency exomes 781/1,456,672 · genomes 621/152,242 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.57%	64
Remaining individualsnot grpmax-eligible	0.0931%	1,074
Admixed American	0.0483%	2,068
Middle Eastern	0.0165%	6,050
European (non-Finnish)	0.011%	9,114
South Asian	0.0055%	18,193
East Asian	0.00223%	44,762

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.Thr216Met
Coding: c.647C>T
MANE Select: NM_001385682
dbSNP: rs76333690
Type: single nucleotide variant
Location: chr3:47918724 (GRCh38)
Gene constraint: LOEUF 0.512 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 43.03

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-thr216met (accessed [today's date]).

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