Is MAPT p.Arg5His (c.14G>A) pathogenic?

MAPT p.Arg5His (c.14G>A) is classified Conflicting classifications of pathogenicity in MAPT (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-07-16). AlphaMissense: likely benign (0.2626); Ultra-rare (popmax 0.0646%, eas); Associated with frontotemporal dementia.

What condition is associated with MAPT p.Arg5His (c.14G>A)?

MAPT p.Arg5His (c.14G>A) is associated with frontotemporal dementia (ClinVar).

How common is MAPT p.Arg5His (c.14G>A) in the general population?

MAPT p.Arg5His (c.14G>A) is ultra-rare (popmax 0.0646%, eas) (gnomAD).

What do computational predictors say about MAPT p.Arg5His (c.14G>A)?

AlphaMissense predicts likely benign (score 0.2626) — an in-silico prediction, not a clinical call.

MAPT p.Arg5His

c.14G>A · rs63750959 · VCV14261

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2626 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0646%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

frontotemporal dementia

Computational evidence

Protein change
AlphaMissense	0.2626	likely benign
REVEL	0.19	benign-leaning
SaProt	LLR -6.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.5	GERP 4.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 29 kb · p 0.0043 · regional, not allelic
Overall
CADD	23.1	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 0.0646% East Asian · 29/44,862 alleles

Filtering AF 0.0462% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.04%

Overall 0.00242% 39/1,611,930 alleles · ultra-rare exomes 34/1,459,828 · genomes 5/152,102 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0646%	1,547
Remaining individualsnot grpmax-eligible	0.00321%	31,166
Admixed American	0.00167%	59,982
European (non-Finnish)	0.000593%	168,539

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: MAPT
Protein: p.Arg5His
Coding: c.14G>A
MANE Select: NM_001377265
dbSNP: rs63750959
Type: single nucleotide variant
Location: chr17:45962351 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.56 · 299 PDB
Residue 5: a UniProt-annotated variant site (in ftd1; reduces the ability of tau to promote microtubule assembly and promotes fibril formation in vitro); a UniProt-annotated variant site (in psnp1; delays assembly initiation and lowers the mass of microtubules formed; but the assembly rate is increased compared to normal tau); the 'disordered' region

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

Disease context

frontotemporal dementia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAPT p.Arg5Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
MAPT p.Arg5Leu Pathogenic ⚠ same residue
MAPT c.1999-10G>T Pathogenic ★★ same condition
MAPT c.2091+16C>T Pathogenic ★★ same condition
MAPT c.2091+3G>A Pathogenic ★★ same condition
MAPT p.Arg798Trp Pathogenic ★★ ⚠ same condition
MAPT p.Asn671Lys Pathogenic ★★ ⚠ same condition
MAPT p.Asn688= Pathogenic ★★ 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/mapt-p-arg5his (accessed [today's date]).

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