Is MMS19 p.Phe420Leu (c.1260C>G) pathogenic?

MMS19 p.Phe420Leu (c.1260C>G) is classified Uncertain significance in MMS19 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-02). AlphaMissense: likely pathogenic (0.9405); Ultra-rare (popmax 0.033%, mid).

How common is MMS19 p.Phe420Leu (c.1260C>G) in the general population?

MMS19 p.Phe420Leu (c.1260C>G) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about MMS19 p.Phe420Leu (c.1260C>G)?

AlphaMissense predicts likely pathogenic (score 0.9405) — an in-silico prediction, not a clinical call.

MMS19 p.Phe420Leu

c.1260C>G · rs766764376 · VCV2375898

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9405 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9405	likely pathogenic · top 6% in MMS19
REVEL	0.299	indeterminate
SaProt	LLR -6.99	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 11 kb · p 0.0082 · regional, not allelic
Overall
CADD	22.2	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 0.033% Middle Eastern · 2/6,058 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00267%

Overall 0.00372% 60/1,613,994 alleles · ultra-rare exomes 53/1,461,674 · genomes 7/152,320 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,029
Admixed American	0.00833%	12,004
Remaining individualsnot grpmax-eligible	0.008%	12,496
European (non-Finnish)	0.0039%	25,650
East Asian	0.00223%	44,880
South Asian	0.0011%	91,080

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: MMS19
Protein: p.Phe420Leu
Coding: c.1260C>G
MANE Select: NM_022362
dbSNP: rs766764376
Type: single nucleotide variant
Location: chr10:97467542 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.00

Full MMS19 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MMS19 p.Ala656= Likely benign ★★ same type
MMS19 p.Gln409Pro Benign ★★ same type
MMS19 p.Ala11Val Uncertain significance ★ ⚠ same type
MMS19 p.Ala121Ser Uncertain significance ★ ⚠ same type
MMS19 p.Ala2Val Uncertain significance ★ ⚠ same type
MMS19 p.Ala324Val Uncertain significance ★ ⚠ same type
MMS19 p.Ala383Val Uncertain significance ★ ⚠ same type
MMS19 p.Ala3Val 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/mms19-p-phe420leu (accessed [today's date]).

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