Is PITRM1 p.Phe618Leu (c.1854C>G) pathogenic?

PITRM1 p.Phe618Leu (c.1854C>G) is classified Benign in PITRM1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-27). AlphaMissense: likely pathogenic (0.8643); Common (popmax 5.81%, mid) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about PITRM1 p.Phe618Leu (c.1854C>G)?

AlphaMissense predicts likely pathogenic (score 0.8643) — an in-silico prediction, not a clinical call.

PITRM1 p.Phe618Leu

Q: How common is PITRM1 p.Phe618Leu (c.1854C>G) in the general population?

PITRM1 p.Phe618Leu (c.1854C>G) is common (popmax 5.81%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1854C>G · rs41305673 · VCV1613440

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8643 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.81%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8643	likely pathogenic · top 9% in PITRM1
REVEL	0.243	benign-leaning
SaProt	LLR -9.47	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 0.52, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 35 kb · p 2.6e-05 · regional, not allelic
Overall
CADD	21.4	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 5.81% Middle Eastern · 339/5,836 alleles

Filtering AF 5.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.1%

Overall 4.28% 67,549/1,579,886 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	7.46%	13
Middle Easterngrpmax	5.81%	17
European (non-Finnish)	4.85%	21
Ashkenazi Jewishnot grpmax-eligible	4.29%	23
Remaining individualsnot grpmax-eligible	4.01%	25
South Asian	3.69%	27
Finnishnot grpmax-eligible	3.35%	30
Admixed American	2.15%	46
African / African-American	0.773%	129
East Asian	0.0452%	2,212

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe618Leu
Coding: c.1854C>G
MANE Select: NM_014889
dbSNP: rs41305673
Type: single nucleotide variant
Location: chr10:3149638 (GRCh38)
Gene constraint: LOEUF 0.997 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.44 · 8 PDB
Residue 618: an α-helix

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

Similar variants

PITRM1 p.Phe618Ser Uncertain significance ★ ⚠ same residue
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

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-phe618leu (accessed [today's date]).

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