Is AMPH p.Arg48Trp (c.142C>T) pathogenic?

AMPH p.Arg48Trp (c.142C>T) is classified Likely benign in AMPH (ClinVar, Single submitter, 1 submitter; last evaluated 2018-08-06). AlphaMissense: likely pathogenic (0.8976); Rare (popmax 0.256%, nfe).

How common is AMPH p.Arg48Trp (c.142C>T) in the general population?

AMPH p.Arg48Trp (c.142C>T) is rare (popmax 0.256%, nfe) (gnomAD).

What do computational predictors say about AMPH p.Arg48Trp (c.142C>T)?

AlphaMissense predicts likely pathogenic (score 0.8976) — an in-silico prediction, not a clinical call.

AMPH p.Arg48Trp

c.142C>T · rs147234401 · VCV722907

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8976 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.256%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8976	likely pathogenic
REVEL	0.362	indeterminate
SaProt	LLR -15.16	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.9	GERP -3.7, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 166 kb · p 1e-06 · regional, not allelic
Overall
CADD	25.6	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 0.256% European (non-Finnish) · 3,021/1,179,742 alleles

Filtering AF 0.248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.245%

Overall 0.199% 3,208/1,613,644 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.256%	391
Remaining individualsnot grpmax-eligible	0.123%	812
Admixed American	0.07%	1,428
Middle Eastern	0.0495%	2,020
African / African-American	0.0427%	2,343
Finnishnot grpmax-eligible	0.025%	3,998
South Asian	0.0165%	6,068
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
East Asian	0.00223%	44,858

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: AMPH
Protein: p.Arg48Trp
Coding: c.142C>T
MANE Select: NM_001635
dbSNP: rs147234401
Type: single nucleotide variant
Location: chr7:38534939 (GRCh38)
Gene constraint: LOEUF 0.697 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.84 · 6 PDB
Residue 48: the bar domain; an α-helix

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

Similar variants

AMPH c.1017+10T>C Likely benign ★★ same type
AMPH p.Thr586Met Likely benign ★★ same type
AMPH p.Ala10Thr Uncertain significance ★ ⚠ same type
AMPH p.Ala169Gly Uncertain significance ★ ⚠ same type
AMPH p.Ala239Ser Uncertain significance ★ ⚠ same type
AMPH p.Ala248Val Uncertain significance ★ ⚠ same type
AMPH p.Ala284Val Uncertain significance ★ ⚠ same type
AMPH p.Ala287Thr Uncertain significance ★ ⚠ same type

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/amph-p-arg48trp (accessed [today's date]).

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