Is PITRM1 p.Ala554Asp (c.1661C>A) pathogenic?

PITRM1 p.Ala554Asp (c.1661C>A) is classified Conflicting classifications of pathogenicity in PITRM1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-22). AlphaMissense: likely benign (0.2145); Rare (popmax 0.548%, afr).

How common is PITRM1 p.Ala554Asp (c.1661C>A) in the general population?

PITRM1 p.Ala554Asp (c.1661C>A) is rare (popmax 0.548%, afr) (gnomAD).

What do computational predictors say about PITRM1 p.Ala554Asp (c.1661C>A)?

AlphaMissense predicts likely benign (score 0.2145) — an in-silico prediction, not a clinical call.

PITRM1 p.Ala554Asp

c.1661C>A · rs12248937 · VCV2044730

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2145 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.548%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2145	likely benign
REVEL	0.281	benign-leaning
SaProt	LLR -7.78	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 2.6	GERP 1.6, phastCons 0.33
Regional constraint	o/e 1.12	unconstrained · MANE · 35 kb · p 2.6e-05 · regional, not allelic
Overall
CADD	20.7	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 0.548% African / African-American · 411/74,988 alleles

Filtering AF 0.504% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.487%

Overall 0.0335% 540/1,611,006 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.548%	182
Middle Eastern	0.363%	275
Remaining individualsnot grpmax-eligible	0.0561%	1,783
Admixed American	0.0402%	2,487
South Asian	0.00443%	22,554
European (non-Finnish)	0.00365%	27,408
Finnishnot grpmax-eligible	0.00157%	63,882

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: PITRM1
Protein: p.Ala554Asp
Coding: c.1661C>A
MANE Select: NM_014889
dbSNP: rs12248937
Type: single nucleotide variant
Location: chr10:3151324 (GRCh38)
Gene constraint: LOEUF 0.997 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.44 · 8 PDB
Residue 554: a disulfide bond; a UniProt-annotated variant site (in)

Full PITRM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PITRM1 p.Thr931Met Pathogenic/Likely pathogenic ★★ same type
PITRM1 p.Ala1003Thr Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala559Val Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala887Val Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala942Val Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala965Thr Uncertain significance ★★ ⚠ same type
PITRM1 p.Arg32Trp Uncertain significance ★★ ⚠ same type
PITRM1 p.Arg545Gln 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/pitrm1-p-ala554asp (accessed [today's date]).

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